Heterocyclic compounds as ligands of the GABAA receptor

ABSTRACT

Disclosed are heterocyclic compounds of the formula                    
     and the pharmaceutically acceptable salts thereof wherein the variables A, V, Y, J, E, X, T, G, Q, W, Z, b, n and m are defined herein. These compounds are highly selective agonists, antagonists or inverse agonists for GABA A  brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABA A  brain receptor.

BACKGROUND OF THE INVENTION

This application claims priority from U.S. Provisional Application Ser.No. 60/223,669, filed Aug. 7, 2000.

FIELD OF THE INVENTION

This invention relates to heterocyclic compounds, and more specificallyto such compounds that bind with high selectivity and high affinity tothe benzodiazepine site of GABA_(A) receptors. This invention alsorelates to pharmaceutical compositions comprising such compounds and tothe use of such compounds in treatment of certain central nervous system(CNS) diseases.

DESCRIPTION OF THE RELATED ART

The GABA_(A) receptor superfamily represents one of the classes ofreceptors through which the major inhibitory neurotransmitter,γ-aminobutyric acid, or GABA, acts. Widely, although unequally,distributed through the mammalian brain, GABA mediates many of itsactions through a complex of proteins called the GABA_(A) receptor,which causes alteration in chloride conductance and membranepolarization.

A number of cDNAs for GABA_(A) receptor subunits have beencharacterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits havebeen identified. It is generally accepted that native GABA_(A) receptorsare typically composed of 2α, 2β, and 1γ subunits (Pritchett & SeeburgScience 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998;6:1-18). Evidence such as message distribution, genome localization andbiochemical study results suggest that the major naturally occurringreceptor combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂(Mohler et.al. Neuroch. Res. 1995; 20(5): 631-636).

Benzodiazepines exert their pharmacological actions by interacting withthe benzodiazepine binding sites associated with the GABA_(A) receptor.In addition to the benzodiazepine site, the GABA_(A) receptor containssites of interaction for several other classes of drugs. These include asteroid binding site, a picrotoxin site, and the barbiturate site. Thebenzodiazepine site of the GABA_(A) receptor is a distinct site on thereceptor complex that does not overlap with the site of interaction forGABA or for other classes of drugs that bind to the receptor (see, e.g.,Cooper, et al., The Biochemical Basis of Neuropharmacology, 6^(th) ed.,1991, pp. 145-148, Oxford University Press, New York). Earlyelectrophysiological studies indicated that a major action of thebenzodiazepines is enhancement of GABAergic inhibition. Compounds thatselectively bind to the benzodiazepine site and enhance the ability ofGABA to open GABA_(A) receptor channels are agonists of GABA receptors.Other compounds that interact with the same site but negatively modulatethe action of GABA are called inverse agonists. Compounds belonging to athird class bind selectively to the benzodiazepine site and yet havelittle or no effect on GABA activity, but can block the action ofGABA_(A) receptor agonists or inverse agonists that act at this site.These compounds are referred to as antagonists.

The important allosteric modulatory effects of drugs acting at thebenzodiazepine site were recognized early and the distribution ofactivities at different receptor subtypes has been an area of intensepharmacological discovery. Agonists that act at the benzodiazepine siteare known to exhibit anxiolytic, sedative, and hypnotic effects, whilecompounds that act as inverse agonists at this site elicit anxiogenic,cognition enhancing, and proconvulsant effects. While benzodiazepineshave a long history of pharmaceutical use as anxiolytics, thesecompounds often exhibit a number of unwanted side effects. These mayinclude cognitive impairment, sedation, ataxia, potentiation of ethanoleffects, and a tendency for tolerance and drug dependence.

GABA_(A) selective ligands may also act to potentiate the effects ofcertain other CNS active compounds. For example, there is evidence thatselective serotonin reuptake inhibitors (SSRIs) may show greaterantidepressant activity when used in combination with GABA_(A) selectiveligands than when used alone.

SUMMARY OF THE INVENTION

This invention provides heterocyclic compounds, such as5,6-Dihydro-4H-1,3a,6-triaza-as-indacenes and related compounds, thatbind with high affinity and high selectivity to the benzodiazepine siteof the GABA_(A) receptor, including human GABA_(A) receptors.

Thus, the invention provides novel compounds of Formula A (shown below),and pharmaceutical compositions comprising compounds of Formula A.

The invention further comprises methods of treating patients sufferingfrom certain CNS disorders with an effective amount of a compound of theinvention. The patient may be a human or other mammal. Treatment ofhumans, domesticated companion animals (pets) or livestock animalssuffering from certain CNS disorders with an effective amount of acompound of the invention is encompassed by the invention.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds. This method comprisesadministering an effective amount of a compound of the invention withanother CNS active compound.

Additionally this invention relates to the use of the compounds of theinvention as probes for the localization of GABA_(A) receptors in tissuesections.

Accordingly, a broad aspect of the invention is directed to compounds ofFormula A:

or a pharmaceutically acceptable salt thereof, wherein:

the b-ring is a 5-9 membered ring;

E represents (CR¹R²)_(k), —CR¹═CR²—, —O—(CR¹R²)_(k)—, —(CR¹R²)_(k)—O—,—N═CR¹—, —CR¹═N—, —NR′—(CR¹R²)_(k)—, or —(CR¹R²)_(k)—NR′—, wherein

R¹ and R² independently represent

hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro,amino, mono- or di-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or

phenyl, pyridyl, phenyl(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl, where eachphenyl or pyridyl is optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- ordi(C₁-C₆)alkylamino;

k is 0, 1, 2, or 3;

R′ represents

hydrogen, C₁-C₆ alkyl, C₂-C₇ alkanoyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₃-C₆)alkyl, or

aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereeach aryl and heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino;

G is oxygen or NH;

J represents (CR⁵R⁶)_(d) where

d is 0 or 1; and

R⁵ and R⁶ together form a carbonyl group; or

R⁵ and R⁶ are independently hydrogen or R₁₀₀,

where each R₁₀₀ is independently selected from halogen, hydroxy, nitro,cyano, R₁₀, amino, —NH(R₁₀), —N(R₁₀)(R₁₀), —COOH, —O(R₁₀), —SO₂NH₂,—SO₂NH(R₁₀), —SO₂N(R₁₀)(R₁₀) —NHCO(R₁₀), —N(R₁₀)CO(R₁₀), —NHCO₂(R₁₀),—N(R₁₀)CO₂(R₁₀), —NHSO₂(R₁₀), —N(R₁₀)SO₂(R₁₀), —SO₂NHCO(R₁₀),—SO₂N(R₁₀)CO(R₁₀) —CONHSO₂(R₁₀), —CON(R₁₀)SO₂(R₁₀), —CONH₂, —CONH(R₁₀),—CON(R₁₀)(R₁₀), —CO₂(R₁₀), —CO(R₁₀), —SR₁₀, SO(R₁₀), —SO2 (R₁₀), arylhaving from 1 to 3 rings, and heteroaryl, said heteroaryl having from 1to 3 rings, 5 to 7 ring members in each ring, and in at least one ofsaid rings from 1 to about 3 heteroatoms selected from nitrogen, oxygenand sulfur, and where each aryl and heteroaryl is optionally substitutedwith 1, 2, or 3 groups independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- ordi(C₁-C₆)alkylamino;

each R₁₀ is independently a straight, branched, or cyclic alkyl grouphaving up to 8 carbon atoms, contains zero or one or more double ortriple bonds, and is optionally substituted with one or moresubstituents independently selected from hydroxy, oxo, halogen, amino,mono- or di-(C₁-C₆)alkylamino, cyano, nitro, C₁-C₆alkoxy, —COOH,—SO₂NH₂, —SO₂NH(C₁-C₆alkyl), —SO₂N(C₁-C₆alkyl)(C₁-C₆alkyl),—NHCO(C₁-C₆alkyl) —N(C₁-C₆alkyl)CO(C₁-C₆alkyl), NHCO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)CO₂(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)SO₂(C₁-C₆alkyl), —SO₂N(C₁-C₆alkyl)CO(C₁-C₆alkyl),—SO₂NHCO(C₁-C₆alkyl), —CON(C₁-C₆alkyl)SO₂(C₁-C₆alkyl),—CONHSO₂(C₁-C₆alkyl), —CONH₂, —CONH(alkyl), —CON(alkyl)(alkyl),—CO₂(alkyl), —CO(alkyl), —SO₀-₂(C₁-C₆alkyl), and C₃-C₇cycloalkyl;

the group

 is the A ring and represents an optionally substituted saturated,partially unsaturated, or aromatic heterocyclic ring containing at leastone nitrogen, oxygen, or sulfur atom,

where the A ring is optionally substituted with up to three groupsindependently selected from R₁₀₀;

V is nitrogen, carbon, or CH;

Y is carbon or CH;

X is hydrogen, hydroxy, amino, mono- or di(C₁-C₆)alkylamino, C₁-C₆alkyl, or C₁-C₆ alkoxy;

T is hydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆) alkylamino,C₁-C₆ alkyl, or C₁-C₆ alkoxy;

Q is a saturated carbocyclic or heterocyclic group, partiallyunsaturated carbocyclic or heterocyclic group, an aryl group, orheteroaryl group, where each group has from 1 to 3 rings where each ringcontains from 3 to 8 ring members, and where each heterocyclic andheteroaryl group contains at least one ring having from 1 to 3heteroatoms selected from nitrogen, oxygen and sulfur; and

where each carbocyclic, heterocyclic, aryl, or heteroaryl group isoptionally substituted with 1, 2, or 3 groups independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, oxo, cyano, nitro,amino, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and mono- ordi(C₁-C₆)alkylamino;

W is a bond, oxygen, NH, sulfur, —CH═CH—, —C≡C₂—, or CR⁷R⁸ where R⁷ andR⁸ are the same or different and represent hydrogen, C₁-C₆ alkyl,halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or C₁-C₆alkoxy(C₁-C₆)alkyl, or CR⁷R⁸ represents C₃-C₇ cycloalkyl;

Z is hydrogen, hydroxy, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkoxy,—CO(C₁-C₆)alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₄)alkoxy, amino, mono- or di(C₁-C₆)alkylamino, orNR₁₁COR₁₂ where R₁₁ and R₁₂ are the same or different and representhydrogen or C₁-C₆ alkyl, or NCOR₁₁R₁₂ represents a heterocycloalkanonering, or

Z is a saturated carbocyclic or heterocyclic group, a partiallyunsaturated carbocyclic or heterocyclic group, an aryl group, or aheteroaryl group, where each group has from 1 to 3 rings where eachsaturated ring contains from 3 to 8 ring members and each aromatic orpartially unsaturated ring contains from 5-8 ring members, and whereeach heterocyclic and heteroaryl group contains at least one ring havingfrom 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; and

where each carbocyclic, heterocyclic, aryl, and heteroaryl group isoptionally substituted with 1, 2, or 3 groups independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and mono- or di(C₁-C₆)alkylamino;

 independently represent saturated carbon chains optionally substitutedwith one or more substituents independently selected from halogen,cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkyl,and C₃-C₇ cycloalkyl;

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3.

The invention also provides intermediates and methods useful forpreparing the compounds of Formula A.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of Formula A include those where G is a nitrogenatom carrying C₁-C₆ alkyl or, preferably, hydrogen.

Other preferred compounds of Formula A are those where the group

(hereinafter “Ar”) represents

phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, thiadiazolyl,quinolinyl, pyrazolyl, isoxazolyl, pyrazinyl, triazolyl(C₁-C₆)alkyl,pyridazinyl, 2-oxo-3-hydropyridyl, oxazole, oxadiazolyl,benzimidazol-5-yl, each of which is optionally substituted with 1, 2 or3 groups independently selected from

halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₃-C₇cycloalkylamino, C₃-C₇ cycloalkyl(C₁-C₃)alkylamino, C₁-C₆alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, furanyl, (4-benzylpiperidinyl)(C₁-C₆)alkoxy,(4-benzylpiperazinyl)(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, trifluoromethyl, C₁-C₆ haloalkoxy,1,3-dioxolanyl, ethyl-methanesulfonylamino(C₁-C₆)alkoxy, 1,4-dioxepinyl,1,4-dioxanyl, phenyoxy, pyrrolidinyl(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, C₁-C₄ alkylamino(C₁-C₄)alkyl, imidazolyl,imidazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkoxy, triazolyl(C₁-C₆)alkyl,benzyloxy(C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, azetidinyl(C₁-C₆)alkoxy,azetidinyl(C₁-C₆)alkyl, C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, C₁-C₆alkanoyl(C₁-C₆)alkoxy, C₁-C₆ alkoxyphenoxy, phenoxy substituted withhalo(C₁-C₆)alkyl, tetrahydrofuranyloxy, oxetanyl(C₁-C₆)alkoxy,oxetanyl(C₁-C₆)alkyl, and 1-benzylimidazolyl(C₁-C₆)alkoxy.

More preferred Ar groups include

phenyl, pyridyl, pyrimidinyl, 2-oxo-3-hydropyridyl, isoxazolyl, andoxazolyl, each of which is optionally substituted with 1 or 2 groupsindependently selected from

halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₃-C₇cycloalkylamino, C₃-C₇ cycloalkyl(C₁-C₃)alkylamino, C₁-C₆alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, furanyl, (4-benzylpiperidinyl)(C₁-C₆)alkoxy,(4-benzylpiperazinyl)(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, trifluoromethyl, C₁-C₆ haloalkoxy,1,3-dioxolanyl, ethyl-methanesulfonylamino(C₁-C₆)alkoxy, 1,4-dioxepinyl,1,4-dioxanyl, phenyoxy, pyrrolidinyl(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, C₁-C₄ alkylamino(C₁-C₄)alkyl, imidazolyl,imidazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkoxy, triazolyl(C₁-C₆)alkyl,benzyloxy(C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, azetidinyl(C₁-C₆)alkoxy,azetidinyl(C₁-C₆)alkyl, C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, C₁-C₆alkanoyl(C₁-C₆)alkoxy, C₁-C₆ alkoxyphenoxy, phenoxy substituted withhalo(C₁-C₆)alkyl, tetrahydrofuranyloxy, oxetanyl(C₁-C₆)alkoxy,oxetanyl(C₁-C₆)alkyl, and 1-benzylimidazolyl(C₁-C₆)alkoxy.

Particularly preferred Ar groups include

phenyl, pyridyl, pyrimidinyl, and 2-oxo-3-hydropyridyl, each of which isoptionally substituted with 1 or 2 groups independently selected from

halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₃-C₇cycloalkylamino, C₃-C₇ cycloalkyl(C₁-C₃)alkylamino, C₁-C₆alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, furanyl, (4-benzylpiperidinyl)(C₁-C₆)alkoxy,(4-benzylpiperazinyl)(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, trifluoromethyl, C₁-C₆ haloalkoxy,1,3-dioxolanyl, ethyl-methanesulfonylamino(C₁-C₆)alkoxy, 1,4-dioxepinyl,1,4-dioxanyl, phenyoxy, pyrrolidinyl(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, C₁-C₄ alkylamino(C₁-C₄)alkyl, imidazolyl,imidazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkoxy, triazolyl(C₁-C₆)alkyl,benzyloxy(C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, azetidinyl(C₁-C₆)alkoxy,azetidinyl(C₁-C₆)alkyl, C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, C₁-C₆alkanoyl(C₁-C₆)alkoxy, C₁-C₆ alkoxyphenoxy, phenoxy substituted withhalo(C₁-C₆)alkyl, tetrahydrofuranyloxy, oxetanyl(C₁-C₆)alkoxy,oxetanyl(C₁-C₆)alkyl, and 1-benzylimidazolyl(C₁-C₆)alkoxy.

Highly preferred substituents on the Ar aryl and heteraryl groupsinclude

halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylamino, C₃-C₇ cycloalkylamino, C₁-C₆alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, pyrrolidinyl(C₁-C₆)alkoxy, C₁-C₄alkylamino(C₁-C₄)alkyl, piperidinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, and C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl.

In addition to compounds of Formula A, the invention also providescompounds of Formula I

and the pharmaceutically acceptable salts thereof, wherein:

J is defined as above with respect to Formula I;

E is defined as above with respect to Formula I and preferablyrepresents —(CR¹R²)_(k)— where R¹ and R² are independently chosen ateach occurrence from hydrogen, halogen, hydroxy, cyano, nitro, amino,haloalkyl, mono or diamino(C₁₋₆)alkyl, C₁₋₆ alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl and C₁₋₆ alkoxy, and k is 0, 1, 2, or 3;

the group

 is a group of the formula:

 represents a saturated, unsaturated or aromatic heterocyclic ringcontaining at least one nitrogen, oxygen or sulfur atom, wherein the UYand VY bonds may be single, double or aromatic bonds,

U is nitrogen, NR^(A), S, or O;

V is nitrogen, carbon or CH;

Y is carbon, or CH;

and said saturated, unsaturated or aromatic heterocyclic ring is chosenfrom:

thienyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl,pyrazinyl, pyridizinyl, piperidinyl, oxazolyl, isoxazolyl, symmetricaland unsymmetrical triazolyl, pyrrolyl, furanyl, diazenyl, triazenyl,1,2,4-triazolone, 4,5-dihydroimidazolyl, and1,4,5,6-tetrahydropyrimidinyl,

each of which is optionally substituted at any available nitrogen byR^(A) and optionally substituted at any available carbon by R³ and R⁴,wherein:

R^(A) is selected from (C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl,or mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, where each aryl and heteroaryl is optionallysubstituted with up to 3 groups independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- anddi(C₁-C₆)alkylamino;

R⁵ and R⁶ are independently chosen from hydrogen, aryl, heteroaryl,halogen, hydroxy, nitro, cyano, C₁₋₆alkyl₁, amino, —COOH,—O(C₁₋₆alkyl₁), —NH(C₁₋₆alkyl₁), —N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁), —SO₂NH₂,—SO₂NH(C₁₋₆alkyl₁), —SO₂N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁),—N(C₁₋₆alkyl₁)CO(C₁₋₆alkyl₁), N(C₁₋₆alkyl₁)CO₂(C₁₋₆alkyl₁),—NHSO₂(C₁₋₆alkyl₁), —N(C₁₋₆alkyl₁)SO₂(C₁₋₆alkyl₁), —SO₂NHCO(C₁₋₆alkyl₁),—CONHSO₂(C₁₋₆alkyl₁), —CONH(C₁₋₆alkyl₁), —CON(C₁₋₆alkyl₁)(C₁₋₆alkyl₁),—CO₂(C₁₋₆alkyl₁), —CO(C₁₋₆alkyl₁) and —SO₀₋₂(C₁₋₆alkyl₁),

wherein C₁₋₆alkyl₁ is independently chosen at each occurrence and isstraight branched or cyclic, may contain one or two double or triplebonds, and is unsubstituted or substituted with one or more substituentsselected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy,carbocylic or heterocyclic group, —COOH, —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₂N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)CO(C₁₋₄alkyl),N(C₁₋₄alkyl)CO₂(C₁₋₄alkyl), —NHSO₂(alkyl), —N(C₁₋₄alkyl)SO₂(C₁₋₄alkyl),—SO₂NHCO(C₁₋₄alkyl), —CONHSO₂(C₁₋₄alkyl), —CONH(C₁₋₄alkyl),—CON(C₁₋₄alkyl)(C₁₋₄alkyl), —CO₂(C₁₋₄alkyl), —CO(C₁₋₄alkyl), and-SO₀₂(C₁₋₄alkyl);

R³ and R⁴ are independently chosen at each occurrence, and are definedthe same as R⁵ and R⁶;

X is chosen from hydrogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆alkoxy;

T is chosen from hydrogen, halogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆alkoxy;

Q is a phenyl, naphthyl, quinolinyl, thienyl, pyridyl, pyrimidinyl,pyrazinyl, oxazolyl, isoxazolyl, symmetrical or unsymmetricaloxadiazolyl, symmetrical or unsymmetrical thiadiazolyl, symmetrical orunsymmetrical triazolyl, pyrazolyl, furanyl, diazenyl, triazenyl, ortriazolopyrazinyl group;

each of which may be unsubstituted or substituted with up to threesubstituents independently selected from i) and ii) wherein

i) represents hydroxy, cyano, halogen, nitro, amino, mono ordi(C₁₋₆)alkylamino, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,trifluoromethyl, or trifluoromethoxy;

ii)represents straight or branched chain C₁₋₆alkyl optionally containingheteroatoms and optionally substituted with one or more carbocyclic orheterocyclic group;

W is hydrogen, oxygen, nitrogen, sulfur, or CR⁷R⁸ where R⁷ and R⁸ arethe same or different and represent hydrogen, straight or branched chainC₁₋₆alkyl, or R⁷ and R⁸ may be taken together to represent a cyclicmoiety having 3-7 carbon atoms;

Z is hydrogen, hydroxy, straight or branched chain C₁₋₆alkoxy,C₃₋₇cycloalkyl, C₃₋₇cycloalkyl(C₁₋₃alkoxy), amino, mono or diC₁₋₆alkylamino, a carbocyclic or heterocylic group, or NR⁹COR₁₀ where R⁹and R₁₀ are the same or different and represent hydrogen or straight orbranched chain C₁₋₆alkyl, or R⁹ and R₁₀ may be joined to from a C₃₋₇cycloalkyl ring, or

Z is a phenyl, napthyl, quinolinyl, thienyl, thiazolyl, pyridyl,pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl, piperidinyl,oxazolyl, isoxazolyl, symmetrical or unsymmetrical thiadiazolyl,symmetrical or unsymmetrical triazolyl, symmetrical or unsymmetricaloxadiazolyl, pyrrolyl, furanyl, pyrimidinyl, diazenyl, triazenyl,1,2,4-triazolone, 4,5-dihydroimidazolyl, or1,4,5,6-tetrahydropyrimidinyl group;

 represent a carbon chain optionally substituted with hydrogen, halogen,cyano, nitro, amino, mono or di C₁₋₆alkylamino, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, trifluoromethyl, trifluoromethoxy, straight orbranched chain C₁₋₆alkyl, or C₃₋₇cycloalkyl, and

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3.

In preferred embodiments of Formula I,

R⁵ and R⁶ are independently chosen from hydrogen, aryl where aryl isdefined as above with respect to Formula A, heteroaryl where heteroarylis defined as above with respect to Formula A, halogen, hydroxy, nitro,cyano, C₁₋₆alkyl₁, amino, —COOH, —O(C₁₋₆alkyl₁), —NH(C₁₋₆alkyl₁),—N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁), —SO₂NH₂, —SO₂NH(C₁₋₆alkyl₁),—SO₂N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁), —N(C₁₋₆alkyl₁)CO(C₁₋₆alkyl₁),N(C₁₋₆alkyl₁)CO₂(C₁₋₆alkyl₁), —NHSO₂(C₁₋₆alkyl₁), —N(C₁₋₆alkyl₁)SO₂(C₁₋₆alkyl₁), —SO₂NHCO(C₁₋₆alkyl₁), —CONHSO₂(C₁₋₆alkyl₁),—CONH(C₁₋₆alkyl₁), —CON(C₁₋₆alkyl₁)(C₁₋₆alkyl₁), —CO₂(C₁₋₆alkyl₁),—CO(C₁₋₆alkyl₁) and —SO₀₋₂(C₁₋₆alkyl₁),

wherein C₁₋₆alkyl₁ is independently chosen at each occurrence and isstraight branched or cyclic, may contain one or two double or triplebonds, and is unsubstituted or substituted with one or more substituentsselected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy,carbocylic or heterocyclic group, —COOH, —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₂N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)CO(C₁₋₄alkyl),N(C₁₋₄alkyl)CO₂(C₁₋₄alkyl), —NHSO₂₍alkyl), —N(C₁₋₄alkyl)SO₂(C₁₋₄alkyl),—SO₂NHCO(C₁₋₄alkyl), —CONHSO₂(C₁₋₄alkyl), —CONH(C₁₋₄alkyl),—CON(C₁₋₄alkyl)(C₁₋₄alkyl), —CO₂(C₁₋₄alkyl), —CO(C₁₋₄alkyl), and—SO₀₋₂(C₁₋₄alkyl);

R³ and R⁴ are independently selected at each occurrence, and are definedthe same as R⁵ and R⁶.

Preferably R³, R⁴, R⁵, and R⁶ are independently hydrogen, halogen,hydroxy, nitro, cyano, C₁₋₆alkyl₁, amino, —COOH, —O(C₁₋₆alkyl),—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)(C₁₋₆alkyl), —SO₂NH₂, —SO₂NH(C₁₋₆alkyl),—SO₂N(C₁₋₆alkyl)(C₁₋₆alkyl), —N(C₁₋₆alkyl)CO(C₁₋₆alkyl),N(C₁₋₆alkyl)CO₂(C₁₋₆alkyl), —NHSO₂(C₁₋₆alkyl), —N(C₁₋₆alkyl)SO₂(C₁₋₆alkyl), —SO₂NHCO(C₁₋₆alkyl), —CONHSO₂(C₁₋₆alkyl),—CONH(C₁₋₆alkyl), —CON(C₁₋₆alkyl)(C₁₋₆alkyl), —CO2(C₁₋₆alkyl),—CO(C₁₋₆alkyl) and —SO₀₂(C₁₋₆alkyl), wherein each C₁₋₆alkyl isindependently unsubstituted or substituted with one or more substituentsselected from hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy,carbocylic or heterocyclic group, —COOH, —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₂N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)CO(C₁₋₄alkyl),N(C₁₋₄alkyl)CO₂(C₁₋₄alkyl), —NHSO₂(alkyl), —N(C₁₋₄alkyl) SO₂(C₁₋₄alkyl),—SO₂NHCO(C₁₋₄alkyl), —CONHSO₂(C₁₋₄alkyl), —CONH(C₁₋₄alkyl),—CON(C₁₋₄alkyl)(C₁₋₄alkyl), —CO2(C₁₋₄alkyl), —CO(C₁₋₄alkyl), and—SO₀₋₂(C₁₋₄alkyl).

More preferably, R³, R⁴, R⁵, and R⁶ are independently hydrogen, halogen,hydroxy, nitro, cyano, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, mono- ordi(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl orhalo(C₁-C₆)alkyl.

In one embodiment, W is a bond, m is 0, and Z is hydrogen, i.e.,

represents hydrogen. Alternatively, this may be viewed as compoundswhere W is hydrogen, m is 0, and Z is absent. Thus, in this embodiment,Q is optionally substituted as defined above and also optionally carriesan optionally substituted carbon chain as defined above.

More preferred Ar groups include phenyl, 2-pyridyl, 2-pyrazinyl, and 3-or 4-pyrazolyl, each of which is optionally mono- or disubstituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, amino, or amino(C₁-C₆)alkyl. Particularly preferredare Ar groups that are unsubstituted or monosubstituted with C₁-C₄alkyl, preferably methyl or ethyl. Specific Ar preferred Ar groupsinclude phenyl substituted at the 2-position (ortho to the point ofattachment) with C₁-C₄ alkyl, preferably methyl or ethyl and 4-pyrazolylsubstituted in the 1-position with C₁-C₆ alkyl, preferably methyl,ethyl, or propyl.

Further provided are compounds of Formula II

and the pharmaceutically acceptable salts thereof,

wherein the variables E, J, R¹, R², R³, R⁴, R⁵, R⁶, k, n, m, T, X, Q, W,and Z are as defined for Formula I.

Compounds of Formula II include compounds where

J is CR⁵R⁶;

E is —(CR¹CR²)_(k)— where —R¹ and R² are hydrogen; k is 1 or 2;

R³, R⁴, R⁵, and R⁶, are independently chosen from hydrogen, halogen,amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and

X and T are both hydrogen (hereinafter compounds of Formula IIa).

Other compounds of Formula II are those where J is CR⁵R⁶, E is —CR¹CR²—and R¹, R², R³, R⁴, R⁵, and R⁶ are hydrogen, and k is 1 (compounds ofFormula IIb).

Particularly preferred compounds of Formula II are compounds of FormulaIIc

In Formula IIc (above) the conformation of the methyl group at the4-position of the indacene ring structure denotes (S) stereochemistry.

Other particularly preferred compounds of Formula II are compounds ofFormula IId

In Formula IId, the conformation of the methyl group at the 4-positionof the indacene ring structure denotes (R) stereochemistry.

Preferred compounds of Formulas IIc and IId are those where

represents phenyl optionally substituted with R_(p) where R_(p) is C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, hydroxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, amino, or amino(C₁-C₆)alkyl.

In another embodiment the invention includes compounds of Formula III

and the pharmaceutically acceptable salts thereof, wherein the variablesE, R¹, R², R³, R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as defined forFormula I.

The definition of the variable R³ at the 2-position of the pyridyl ringis independent of it definition at the 3-position.

Specific compounds of Formula III are those where E is —(CR¹CR²)_(k)—; kis 2 and R¹ and R² are hydrogen (compounds of Formula IIIa). Othercompounds of Formula III are compounds where E is —(CR¹CR²)_(k)—; k is2; R¹ and R² are hydrogen; R³, R⁴, R⁵, and R⁵ are independently chosenat each occurrence from hydrogen, halogen, amino, hydroxy, methyl,ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds ofFormula IIIb). Also particularly included as compounds of Formula IIIare compounds of Formula IIIc and Formula IIId

wherein each R³ is independently hydrogen or methyl.

Preferred compounds of Formulas IIIc and IIId are those where

(“Ar”) represents phenyl or pyridyl optionally substituted with R_(p)where R_(p) is C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, amino, or amino(C₁-C₆)alkyl.Preferably, Ar in IIIc and IIId represents phenyl or 2- or 3-pyridyleach of which is optionally substituted with C₁-C₆ alkyl, or morepreferably unsubstituted or substituted with methyl or ethyl.

The invention also includes compounds of Formula IV

and the pharmaceutically acceptable salts thereof, wherein the variablesE, R¹, R², R³, R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as defined forFormula I. Particular compounds of Formula IV are those compounds whereE is —(CR¹CR²)_(k)—, k is 2 and R¹ and R² are hydrogen (compounds ofFormula IVa). Other compounds of Formula IV are those compounds were Eis —(CR¹CR²)_(k)—, k is 2; R¹ and R² are hydrogen; R³, R⁴, R⁵, and R⁶,are independently chosen at each occurrence from hydrogen, halogen,amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are bothhydrogen (compounds of Formula IVb). Compounds of Formula IVparticularly include compounds where E is —(CR¹CR²)_(k)—, k is 2 and R¹,R², R³, R⁴, R⁵, and R⁶ are all hydrogen (compounds of Formula IVc).

Preferred compounds of Formulas IV, and of IVa-IVc, are those where

(“Ar”) represents phenyl, 2-pyrazinyl, or 2-pyridyl optionallysubstituted with R_(p) where R_(p) is C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, amino, oramino(C₁-C₆)alkyl. Preferably, Ar in Formula IV is phenyl, 2-pyridyl, or2-pyrazinyl, each of which is optionally substituted with C₁-C₆ alkyl,or more preferably unsubstituted or substituted with methyl or ethyl.Still other preferred Ar groups in Formula IV are 3- and 4-pyrazolylgroups substituted in the 1-position with C₁-C₄ alkyl group, preferablymethyl or ethyl.

In another embodiment the invention includes compounds of Formula V

and the pharmaceutically acceptable salts thereof wherein the variablesE, R¹, R², R³, R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as for FormulaI. In a more specific embodiment, the invention includes compounds ofFormula V where E is —(CR¹CR²)_(k)—, k is 2 and R¹ and R² are hydrogen(compounds of Formula Va). Still other compounds of Formula V are thosecompounds where E is —(CR¹CR²)_(k)—, k is 2; R¹ and R² are hydrogen;R^(A) is C₁₋₆alkyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, phenyl, thienyl, pyridyl, pyrimidinyl, or pyrrolyl;R³, R⁴, R⁵, and R⁶, are independently chosen from hydrogen, halogen,amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are bothhydrogen (compounds of Formula Vb). In a still more specific embodimentthe invention includes compounds of Formula V where E is —(CR¹CR²)_(k)—,k is 2, R¹, R², R³, R⁴, R⁵, and R⁶ are all hydrogen; and R^(A) ismethyl, ethyl, or pyridyl.

Yet another embodiment of the invention includes compounds of Formula VI

and the pharmaceutically acceptable salts thereof, wherein the variablesE, R¹, R², R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as defined forFormula I. Particular compounds of Formula VI are compounds where E is—(CR¹CR²)_(k)—, k is 2 and R¹ and R² are both hydrogen (compounds ofFormula VIa). Other compounds of Formula VI are compounds where E is—(CR¹CR²)_(k)—, k is 2; and R¹ and R² are both hydrogen; R⁴, R⁵, and R⁶,are independently chosen from hydrogen, halogen, amino, hydroxy, methyl,ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds ofFormula VIb). A particular embodiment of the invention includescompounds of Formula VI where E is —(CR¹CR²)_(k)—, k is 2; and R¹, R²,R⁵, R⁶, X and T are all hydrogen; and R⁴ is methyl (compounds of FormulaVIc).

In still another embodiment, the invention provides compounds of FormulaVII

and the pharmaceutically acceptable salts thereof, wherein the variablesE, R¹, R², R^(A), R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as definedfor Formula I. Included as compounds of Formula VII are compounds wherek is 2 and R¹ and R² are hydrogen (compounds of Formula VIIa). Moreparticularly, the invention includes compounds of Formula VII where E is—(CR¹CR²)_(k)—, k is 2; R¹ and R² are hydrogen; R^(A) is methyl, ethyl,or pyridyl; R⁴, R⁵, and R⁶, are independently chosen from hydrogen,halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and Tare both hydrogen (compounds of Formula VIIb). The invention alsoparticularly includes compounds of Formula VII where E is—(CR¹CR²)_(k)—, k is 2; R¹, R², R⁴, R⁵, R⁶, X and T are all hydrogen;and R^(A) is methyl (compounds of Formula VIIc).

Further included as compounds of the invention are compounds of FormulaVIII

and the pharmaceutically acceptable salts thereof wherein the variablesE, R¹, R², R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as defined as forFormula I. Such compounds of Formula VIII include compounds where E is—(CR¹CR²)_(k)—, k is 2 and R¹ and R² are both hydrogen (compounds ofFormula VIIIa). In yet another embodiment the invention providescompounds of Formula VIII where k is 2; R¹ and R² are both hydrogen; R⁴,R⁵, and R⁶, are independently chosen from hydrogen, halogen, amino,hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are bothhydrogen (compounds of Formula VIIIb). More particularly, the inventionprovides compounds of Formula VIII where E is —(CR¹CR²)_(k)—, k is 2;R¹, R², R⁵, R⁶, X, and T are all hydrogen; and R⁴ is methyl (compoundsof Formula VIIIc).

For each of Formula IIa, IIb, IIc, IIIa, IIIb, IIIc, IIId, IVa, IVb,IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, andVIIIc the variables n, m, Q, W, and Z are as defined for Formula I.

Alternate embodiments of the invention include compounds of Formula IX,Formula X, Formula XI, and Formula XII (shown below) and thepharmaceutically acceptable salts thereof wherein variables R¹, R², R³,R⁴, R⁵, R⁶, k, n, m, T, X, Q, W, and Z are as defined for Formula I.

Other compounds provided by the invention, but outside the definition ofgeneral Formula I, are compounds of the formula

where Y is nitrogen, and all other variables are as defined for FormulaI.

The invention also provides compounds of the formula B-1:

where the “B-ring” is a 5-9 membered ring containing up to 4 heteroatoms selected from nitrogen, NR^(A), S, and oxygen. The B-ring issaturated, unsaturated or aromatic. All other variables are as definedfor Formula I.

Preferred compounds of B-1 are those where the b-ring has the formula:

wherein

R^(5a) is hydrogen, hydroxy, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, mono- or di(C₁-C₆)alkylamino, or phenyl optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano,nitro, amino, and mono- or di(C₁-C₆)alkylamino.

Other preferred compounds of B-1 are those where the b-ring has theformula

wherein

R⁵ and R⁶ carry the definitions given above with respect to Formula A orFormula I;

M is NR′ or oxygen; and

R^(5a) and R^(5b) are independently

hydrogen, hydroxy, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,amino, or mono- or di(C₁-C₆)alkylamino, or

phenyl, pyridyl, phenyl(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl, where eachphenyl and pyridyl is optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- ordi(C₁-C₆)alkylamino; and

R′ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₃-C₆)alkyl, or

aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereeach aryl and heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino.

More preferred compounds of this group are those where

R⁵ and R⁶ are independently hydrogen or C₁-C₆ alkyl;

M is NR′ where R′ is

hydrogen, C₁-C₆ alkyl, , C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or

aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereeach aryl and heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino; and

R^(5a) and R^(5b) are hydrogen.

Still other more preferred compounds of this group are those where

X and T are hydrogen; and

R^(3a) and each R³ independently represent

hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- ordi(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or

phenyl, pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆ alkyl substitutedwith phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl,pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with oneor two groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, and amino.

Yet other more preferred compounds of this group are those where R′ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ alkyl substituted with phenyl orpyridyl, where each phenyl or pyridyl is optionally substituted withhalogen, hydroxy, amino, C₁-C₆ alkyl or C₁-C₆ alkoxy.

Particularly preferred compounds of this group are those where R⁵ and R⁶are independently hydrogen or C₁-C₆ alkyl;

M is oxygen; and

R^(5a) and R^(5b) are hydrogen.

Also within formula B-1, there are included Formulas XIII and XIV.

wherein

X, T, Q, n, W, m, and Z are as defined above with respect to Formula Aor Formula I;

D is nitrogen or CR³ where

R^(3a) and each R³ independently represents hydrogen, halogen, hydroxy,cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆alkoxy, amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl,aryl, heteroaryl, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, or C₁-C₆ alkyl substituted witharyl or heteroaryl; and

R^(5a) is hydrogen, hydroxy, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, mono- or di(C₁-C₆)alkylamino, or phenyl optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano,nitro, amino, and mono- or di(C₁-C₆)alkylamino.

In a specific aspect of Formula XIII, D is CR³ (hereinafter FormulaXIII-a). Preferred compounds of XIII-a include those where each R³ ishydrogen, R^(5a) and T are hydrogen, X is hydrogen or C₁-C₆ alkyl,preferably hydrogen or methyl, and R^(3a) is C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl. Particularlypreferred R^(3a) groups in Formula XIII-a are hydroxy, and morepreferably, C₁-C₃ alkoxy.

In another specific aspect of Formula XIII, D is nitrogen (hereinafterFormula XIII-b). Preferred compounds of XIII-b include those where R³ ishydrogen, R^(5a) and T are hydrogen, X is hydrogen or C₁-C₆ alkyl,preferably hydrogen or methyl, and R^(3a) is C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl.

Preferred compounds of Formulas XIII-a and XIII-b are those where

(“Ar”) represents phenyl, pyrazolyl, or pyridyl, each of which isoptionally substituted with R_(p) where R_(p) is C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, amino,or amino(C₁-C₆)alkyl. More preferably, Ar is 3- or4-pyrazolyl or 2- or3-pyridyl, each of which is preferably substituted with C₁-C₆ alkyl,preferably methyl or ethyl, or more preferably unsubstituted.Particularly preferred Ar groups are 3-pyrazolyl and 2-pyridyl.

Preferred compounds of Formulas XIII-a and XIII-b are those where R^(5a)is hydrogen.

Other preferred compounds of Formulas XIII-a and XIII-b are those whereR^(5a) is hydrogen;

X and T are hydrogen; and

R^(3a) and each R³ independently represents

hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- ordi(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, ornitro(C₁-C₆)alkyl, or

phenyl, pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆ alkyl substitutedwith phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl,pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with oneor two groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, and amino.

Still other preferred compounds of Formulas XIII-a and XIII-b are thosewhere R^(5a) is hydrogen;

R³ is hydrogen and R^(3a) is hydrogen, C₁-C₆ alkyl, halogen, hydroxy,C₁-C₆ alkoxy, amino or mono- or di(C₁-C₆)alkylamino.

Yet other preferred compounds of Formulas XIII-a and XIII-b are thosewhere R^(5a) is hydrogen; and R is hydrogen, C₁-C₆ alkoxy, hydroxy, orC₁-C₆ alkoxy.

As noted above, within formula B-1, there is included Formula XIV.

wherein

X, T, Q, n, W, m, and Z are as defined above with respect to Formula Aor Formula I;

M is NR′ or oxygen;

D is nitrogen or CR³ where

R^(3a) and each R³ independently represents hydrogen, halogen, hydroxy,cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆alkoxy, amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl,aryl, heteroaryl, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, or C₁-C₆ alkyl substituted witharyl or heteroaryl;

R^(5a) and R^(5b) are independently

hydrogen, hydroxy, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,amino, or mono- or di(C₁-C₆)alkylamino, or

phenyl, pyridyl, phenyl(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl, where eachphenyl and pyridyl is optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- ordi(C₁-C₆)alkylamino; and.

R′ is

hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or

aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereeach aryl and heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino.

In a specific aspect of Formula XIV, D is CR³ (hereinafter FormulaXIV-a).

In another specific aspect of Formula XIV, D is nitrogen (hereinafterFormula XIV-b).

Preferred compounds of this group are those where

R⁵ and R⁶ are independently hydrogen or C₁-C₆ alkyl;

M is NR′ where R′ is

hydrogen, C₁-C₆ alkyl, C₂-C₇ alkanoyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or

aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereeach aryl and heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino; and

R^(5a) and R^(5b) are hydrogen.

Still other preferred compounds of this group of Formulas XIV-a andXIV-b are those where

X and T are hydrogen; and

R^(3a) and each R³ independently represent

hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- ordi(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or

phenyl, pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆ alkyl substitutedwith phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl,pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with oneor two groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, and amino.

Yet other preferred compounds of this group are those where each R³ ishydrogen and R^(3a) is hydrogen, C₁-C₆ alkyl, halogen, hydroxy, C₁-C₆alkoxy, amino or mono- or di(C₁-C₆)alkylamino.

Still other preferred compounds within this group are those where R^(3a)is hydrogen, C₁-C₆ alkoxy, hydroxy, or C₁-C₆ alkoxy.

Other preferred compounds within this group are those where R^(5a) andR^(5b) are hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkyl substituted with phenylor pyridyl, where each phenyl or pyridyl is optionally substituted withhalogen, hydroxy, amino, C₁-C₆ alkyl or C₁-C₆ alkoxy.

Still other preferred compounds within this group are those where

R⁵ and R⁶ are independently hydrogen or C₁-C₆ alkyl;

M is oxygen; and

R^(5b) and R^(5b) are hydrogen.

Yet preferred compounds within this group are those wherein

X and T are hydrogen; and

R^(3a) and each R³ independently represent

hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- ordi(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, ornitro(C₁-C₆)alkyl, or

phenyl, pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆ alkyl substitutedwith phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl,pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with oneor two groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, and amino.

Still other preferred compounds within this group are those wherein eacheach R³ is hydrogen and R^(3a) is hydrogen, C₁-C₆ alkyl, halogen,hydroxy, C₁-C₆ alkoxy, amino or mono- or di(C₁-C₆)alkylamino.

Still other preferred compounds within this group are those where R^(3a)is hydrogen, C₁-C₆ alkoxy, hydroxy, or C₁-C₆ alkoxy.

Preferred compounds of XIV-a (D is CR³) include those where M is NR′where R′ is hydrogen, C₁-C₆ alkyl, preferably C₁-C₃ alkyl, each R³ ishydrogen, R^(5a) R^(5b), and T are hydrogen, X is hydrogen or C₁-C₆alkyl, preferably hydrogen or methyl, R⁵ and R⁶ are independentlyhydrogen or C₁-C₂ alkyl, more preferably hydrogen or methyl, and R^(3a)is C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl. Preferred R³a groups in Formula XIV-a are hydroxyand C₁-C₃ alkoxy. Particularly preferred R′ groups are

Other preferred compounds of XIV-b (D is nitrogen) include those where Mis NR′ where R′ is hydrogen or acetyl, R³ is hydrogen, R^(5a), R^(5b),and T are hydrogen, X is hydrogen or C₁-C₆ alkyl, preferably hydrogen ormethyl, and R^(3a) is C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl.

Preferred compounds of Formulas XIV-a and XIV-b are those where

(“Ar”) represents phenyl, pyrazolyl, or pyridyl, each of which isoptionally substituted with R_(p) where R_(p) is C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, amino,or amino(C₁-C₆)alkyl. More preferably, Ar is 3- or4-pyrazolyl or 2- or3-pyridyl, each of which is preferably substituted with C₁-C₆ alkyl,preferably methyl or ethyl, or more preferably unsubstituted.Particularly preferred Ar groups are 3-pyrazolyl and 2-pyridyl.

Further provided by the invention are intermediates useful insynthesizing compounds of the invention. Thus, the invention encompassescompounds of the following formulas

wherein

the A-ring, Y, V, E, R5, R⁶, X and T carry the definitions assigned withrespect to Formula A; and

R^(B) is a group forming an ester, e.g., C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, and thelike.

Preferred R^(B) groups are hydrogen, methyl, ethyl and benzyl.

Specific compounds of Formula XV include those where U is nitrogen,NR^(A), S, or O; V is nitrogen, carbon or CH; and Y is carbon, or CH;

Preferred compounds of Formula XV are those where the A-ring represents

Preferred R^(A), R³, and R⁴ groups on compounds of Formula XV arehydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy.

Preferred compounds of XV include those of Formulas XVI and XVII.

wherein:

R⁴ is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl,methoxy, and ethoxy.

wherein:

R^(A) is chosen from hydrogen, methyl, ethyl, and phenyl; and

wherein:

R³ is hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, orethoxy.

The invention encompasses compounds of Formulas I-1, I-2, I-3, I-4, andI-5.

wherein:

A is oxygen or sulfur;

E, R⁵, R⁶, and T carry the definition assigned with respect to Formula Iand Formula A; and

R^(B) is a group forming an ester, e.g., C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, and thelike.

Preferred R^(B) groups are hydrogen, methyl, ethyl and benzyl.

wherein

B is —SCH₃ or —NH(CH₂)CH(OCH₃)₂; and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl.

wherein

E, R⁵, R⁶, and T carry the definition assigned with respect to Formula Iand Formula A; and

R³ and R⁴ independently carry the same definitions as R⁵ and R⁶; and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl.

wherein:

E, X, R⁵, R⁶, and T carry the definition assigned with respect toFormula I and Formula A; and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl.

wherein:

E, R⁵, R⁶, and T carry the definition assigned with respect to Formula Iand Formula A; and

R³ is defined the same as R⁵ and R⁶; and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl;

R^(C) is independently chosen at each occurrence from t-butoxycarbonyl,phenyl, phenylsulfonyl, C₁-C₆ alkylsulfonyl, and ethylcarbamoyl.

Each of the synthetic schemes provided in the “Preparation of Compounds”section (below) involves the reaction of a ester compound to form anamide. For example, see step 11 of Scheme 1. Thus, the inventionprovides ester intermediates of Formula XX

wherein

E and J carry the definitions assigned with respect to Formula A andFormula I;

R¹ and R² are independently chosen at each occurrence from hydrogen,halogen, hydroxy, cyano, nitro, amino, alkyl, alkenyl, alkynyl,haloalkyl, and mono or dialkylamino, mono or dialkylaminoalkyl, alkoxy,and k is 0, 1, 2, or 3;

the group

 referred to as the “A-ring” represents an optionally substitutedsaturated, unsaturated or aromatic heterocyclic ring containing at leastone nitrogen, oxygen or sulfur atom, wherein the VY bond is a single,double, or aromatic bond;

V is nitrogen, carbon, or CH;

Y is carbon, or CH;

R⁵ and R⁶ may be taken together to form a carbonyl group; or

R⁵ and R⁶ are independently chosen from hydrogen, halogen, hydroxy,nitro, cyano, alkyl₁, amino, —COOH, —O(alkyl₁), —SO₂NH₂, —SO₂NH(alkyl₁),—SO₂N(alkyl₁)(alkyl₁), —N(alkyl₁)CO(alkyl₁), N(alkyl₁)CO₂(alkyl₁),—NHSO₂(alkyl₁), —N(alkyl₁)SO₂(alkyl₁), —SO₂NHCO(alkyl₁),—CONHSO₂(alkyl₁), —CONH(alkyl₁), —CON(alkyl₁)(alkyl₁), —CO₂(alkyl₁),—CO(alkyl₁), —SO₀₋₂(alkyl₁), optionally substituted carbocyclic aryl andoptionally substituted heteroaryl groups having from 1 to 3 rings, 3 to8 members in each ring and from 1 to 3 heteroatoms;

wherein alkyl₁ is independently chosen at each occurrence and isstraight branched or cyclic, may contain one or two double or triplebonds, and is unsubstituted or substituted with one or more substituentsselected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy,—COOH, —SO₂NH₂, —SO₂NH(alkyl), —SO₂N(alkyl)(alkyl), —N(alkyl)CO(alkyl),N(alkyl)CO₂(alkyl), —NHSO₂(alkyl), —N(alkyl)SO₂(alkyl), —SO₂NHCO(alkyl),—CONHSO₂(alkyl), —CONH(alkyl), —CON(alkyl)(alkyl), —CO₂(alkyl),—CO(alkyl) —SO₀₋₂(alkyl)

X is chosen from hydrogen, hydroxy, amino, alkyl, and alkoxy;

T is chosen from hydrogen, halogen, hydroxy, amino, alkyl, and alkoxy;and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl.

Preferred compounds of Formula XX include compounds wherein E is—(CR¹R²)_(k)—, —CR¹═CR²—, —N═CR¹—, or —NR′—(CR¹R²)_(k)—. Particularlypreferred are —(CR¹R²)_(k)—, —N═CR¹—, and —NR′—(CR¹R²)_(k)—.

Other preferred compounds of Formula XX are those where J is—(CR⁵R⁶)_(d)— where d is 1.

Still other preferred compounds of Formula XX are those where E is—N═CR¹— and d is 0, or —NR′—(CR¹R²)_(k)— where d is 0 and k is 1.

Preferred compounds of Formula XX include compounds wherein

E and J carry the definitions given with respect to Formulas A and I;

R¹ and R² are independently chosen at each occurrence from hydrogen,halogen, hydroxy, cyano, nitro, amino, haloalkyl, mono ordiamino(C₁₋₆)alkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₁₋₆alkoxy, and k is 0, 1, 2, or 3;

the group

or the “A-ring” is a group of the formula:

 which is a saturated, unsaturated or aromatic heterocyclic ringcontaining at least one nitrogen, oxygen or sulfur atom, wherein the UYand VY bonds may be single, double or aromatic bonds,

U is nitrogen, NR^(A), S, or O;

V is nitrogen, carbon or CH;

Y is carbon, or CH;

and said saturated, unsaturated or aromatic heterocyclic ring is chosenfrom:

thienyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl,pyrazinyl, pyridizinyl, piperidinyl, oxazolyl, isoxazolyl, symmetricaland unsymmetrical triazolyl, pyrrolyl, furanyl, diazenyl, triazenyl,1,2,4-triazolone, 4,5-dihydroimidazolyl, and1,4,5,6-tetrahydropyrimidinyl,

each of which is optionally substituted at any available nitrogen byR^(A) and optionally substituted at any available carbon by R³ and R⁴,wherein:

R^(A) is chosen from hydrogen, C₁₋₆alkyl₁, optionally substitutedcarbocyclic aryl and optionally substituted heteroaryl groups havingfrom 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3heteroatoms;

R⁵ and R⁶ are independently chosen from hydrogen, halogen, hydroxy,nitro, cyano, C₁₋₆alkyl₁, amino, —COOH, —O(C₁₋₆alkyl₁), —NH(C₁₋₆alkyl₁),—N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁), —SO₂NH₂, —SO₂NH(C₁₋₆alkyl₁),—SO₂N(C₁₋₆alkyl₁)(C₁₋₆alkyl₁),—N(C₁₋₆alkyl₁)CO(C₁₋₆alkyl₁)N(C₁₋₆alkyl₁)CO₂(C₁₋₆alkyl₁)NHSO₂(C₁₋₆alkyl₁), —N(C₁₋₆alkyl₁) SO₂(C₁₋₆alkyl₁), —SO2NHCO(C₁₋₆alkyl₁),—CONHSO₂(C₁₋₆alkyl₁), —CONH(C₁₋₆alkyl₁), —CON(C₁₋₆alkyl₁)(C₁₋₆alkyl₁),—CO₂(C₆alkyl₁), —CO(C₁₋₆alkyl₁) and —SO₀₋₂(C₁₋₆alkyl₁),

wherein C₁₋₆alkyl₁ is independently chosen at each occurrence and isstraight branched or cyclic, may contain one or two double or triplebonds, and is unsubstituted or substituted with one or more substituentsselected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy,carbocylic or heterocyclic group, —COOH, —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₂N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)CO(C₁₋₄alkyl),N(C₁₋₄alkyl)CO₂(C₁₋₄alkyl), —NHSO₂(alkyl), —N(C₁₋₄alkyl) SO₂(C₁₋₄alkyl),—SO₂NHCO(C₁₋₄alkyl), —CONHSO₂(C₁₋₄alkyl), —CONH(C₁₋₄alkyl),—CON(C₁₋₄alkyl)(C₁₋₄alkyl) —CO₂(C₁₋₄alkyl), —CO(C₁₋₄alkyl), and—SO₀₋₂(C₁₋₄alkyl);

R³ and R⁴ are independently chosen at each occurrence, and are definedthe same as R⁵ and R⁶;

X is chosen from hydrogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆alkoxy;

T is chosen from hydrogen, halogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆alkoxy; and

R^(B) is chosen from hydrogen, methyl, ethyl and benzyl.

Such compounds will be referred to as compounds of Formula XXa.

The ester intermediates of this invention differ primarily in the typeof “A-ring” present although other differences may be present. one classof intermediates provided by this invention is represented by FormulaXXI

wherein J, E, R¹, R², R³, R⁴, R⁵, R⁶, J, E, k, X, T, and R^(B) are asdefined for Formula XXa. Preferred intermediates of Formula XXI arethose compounds wherein R^(B) is defined as for Formula XXa; E is—(CR¹R²)_(k)—, k is 1 or 2; R¹ and R² are both hydrogen; and R³, R⁴, R⁵,and R⁶, are independently chosen from hydrogen, halogen, amino, hydroxy,methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of FormulaXXIa).

The invention further provides ester intermediates having a pyridyl“A-ring” such as compounds of Formula XXII

wherein R³ is independently selected at each occurrence and is asdefined as for Formula XXa and R¹, R², R³, R⁴, R⁵, E, J, k, X, T, andR^(B) are also defined as for Formula XXa.

Particularly, the invention provides as compounds of Formula XXII,compounds where R^(B) is defined as for Formula XXa; E is —(CR¹R²)_(k)—;R¹, R², R³, R⁵, R⁶, X, and T are all hydrogen; R³ is hydrogen at the 3-and 4-positions of the “A-ring” pyridyl group, and is chosen fromhydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy atthe 2-position of this “A-ring” pyridyl group (hereinafter compounds ofFormula XXIIa).

Also provided as compounds of Formula XXII, are compounds where E is—(CR¹R²)_(k)—; R^(B) is defined as for Formula XXa; R¹, R², R³, R⁵, R⁶,X, and T are all hydrogen; R³ is hydrogen at the 2- and 4-positions ofthe “A-ring” pyridyl group, and is chosen from hydrogen, halogen, amino,hydroxy, methyl, ethyl, methoxy, and ethoxy at the 3-position of this“A-ring” pyridyl group (hereinafter compounds of Formula XXIIb).

The invention provides intermediates of Formula XXIII having apyrimidinyl “A-ring”

wherein R¹, R², R³, R⁴, R⁵, R⁶, E, k, X, T, and R are as defined inclaim XXa. Preferred compounds of Formula XXIII include compounds whereE is —(CR¹R²)_(k)—; k is 2; R¹, R², R³, R⁵, R⁶, X, and T are allhydrogen; R^(B) is defined as for Formula XXa; and R⁴ is chosen fromhydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy(hereinafter compounds of Formula XXIIIa).

In one embodiment the invention provides compounds of Formula XXIV wherethe “A-ring” is a pyrrole

wherein R^(A), R¹, R², R⁴, R⁵, R⁶, E, k, X, T, and R^(B) are as definedin Formula XXa. Preferred compounds of Formula XXIV include compoundswhere E is —(CR¹R²)_(k)—; k is 2; R^(A) is chosen from hydrogen, methyl,ethyl, and phenyl; R^(B) is as defined in Formula XXa; and R¹, R², R⁴,R⁵, R⁶, X, and T are all hydrogen (hereinafter compounds of FormulaXXIVa).

The invention further includes compounds of Formula XXV

wherein R^(A), R¹, R², R³, R⁴, R⁵, R⁶, E, k, X, T, and R^(B) are asdefined for Formula XXa. Also included as compounds of Formula XXV arecompounds wherein E is —(CR¹R²)_(k)—; k is 2; R^(A), R¹, R², R⁴, R⁵, R⁶,k, X, and T are all hydrogen; R^(B) is as defined for Formula XXa; andR⁴ is from chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl,methoxy, and ethoxy (hereinafter compounds of Formula XXVa).

In yet another embodiment the invention provides ester intermediates ofFormula XXVI having thiazole “A-rings”

wherein R¹, R², R³, R⁵, R⁶, E, k, X, T, and R^(B) are as defined forFormula XXa. Preferably compounds of this class are those compoundswhere E is —(CR¹R²)_(k)—; k is 2; R¹, R², R⁵, R⁶, X, and T are hydrogen;R^(B) is as defined for Formula XXa; and R³ is chosen from R³ is chosenfrom hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, andethoxy (hereinafter compounds of Formula XXVIa).

Another class of intermediates of the invention is represented bycompounds of Formula XXVII having and isoxazole “A-ring”

wherein R¹, R², R³, R⁵, R⁶, E, k, X, T, and R^(B) are as defined in forFormula XXa. Preferably compounds of this class are those compoundswhere E is —(CR¹R²)_(k)—; k is 2; R¹, R², R⁵, R⁶, X, and T are hydrogen;R³ is as defined for Formula XXa; and R³ is chosen from R³ is chosenfrom hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, andethoxy (hereinafter compounds of Formula XXVIIa).

In a number of the synthetic steps used to generate compounds of theinvention novel protected intermediates are used. Such protectedintermediates include compounds of Formula XXX useful in the synthesisof compounds of the invention having an imidazole “A-ring”

wherein A is oxygen or sulfur; J, E, k, R¹, R², R⁵, R⁶, R^(B) and T areas defined for Formula XXa. Preferably, E is —(CR¹R²)_(k)—; and d is 1or 2, more preferably 1.

Another class of protected intermediates useful in the synthesis ofcompounds of the invention having an imidazole “A-ring” are compounds ofFormula XXXI

wherein B is —SCH₃ or —NH(CH₂)CH(OCH₃)₂ and J, E, k, R¹, R², R⁵, R⁶,R^(B) and T are as defined for Formula XXa. Preferably, E is—(CR¹R²)_(k)—; and d is 1 or 2, more preferably 1.

Also provided are compounds of Formula XXXII

wherein all variables present in compounds of Formula XXXII are definedas for compounds of Formula XXa. Preferably, E is —(CR¹R²)_(k)—; and dis 1 or 2, more preferably 1.

Other classes of novel intermediates provided by the invention areintermediates have BOC and TMS protecting groups (or analogues of suchgroups) such as compounds of Formula XXXIII

wherein R^(C) is chosen from t-butoxycarbonyl, phenyl, alkylsulfonyl,and ethylcarbamoyl; R^(Z) is hydrogen or bromo; and J, E, k, R^(B), R¹,R², R⁵, R⁶, and T are defined as for compounds of Formula XXa.

Preferably, E is —(CR¹R²)_(k)—; and d is 1 or 2, more preferably 1.

Further provided are compounds of Formula XXXIV

R^(C) is chosen from t-butoxycarbonyl, phenyl, phenylsulfonyl,alkylsulfonyl, and ethylcarbamoyl;

R^(D) is chosen from trimethylsilyl and t-butyldimethylsilyl; and

J, E, k, R^(B), R¹, R², R⁵, R⁶, and T are defined as for Formula XXa.

Preferably, E is —(CR¹R²)_(k)—; and d is 1 or 2, more preferably 1.

Further, the invention provides as intermediates compounds of FormulaXXXV

wherein E, J, k, R^(B), R¹, R², R⁵, R⁶, X and T are as defined forFormula XXa. In compounds of XXXV, E is preferably —(CR¹R²)_(k)— and dis 1 or 2, more preferably 1.

Finally, the invention provides compounds of Formula XXXVI asintermediates

R^(C) is independently chosen at each occurrence from t-butoxycarbonyl,phenyl, phenylsulfonyl, alkylsulfonyl, and ethylcarbamoyl and all othervariables are as defined for compounds of Formula XXa.

In preferred compounds of XXXVI, Preferably, E is preferably—(CR¹R²)_(k)— and d is 1 or 2, more preferably 1.

This invention relates to heterocyclic compounds, such as5,6-Dihydro-4H-1,3a,6-triaza-as-indacenes,3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylicacids, 4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acids, 3,8,10-triaza-benzo[e]azulene-1-carboxylic acids,1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acids,1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid phenyl amide andrelated compounds, that bind with high affinity to the benzodiazepinesite of GABA_(A) receptors, including human GABA_(A) receptors. Thisinvention also includes such compounds that bind with high selectivityto the benzodiazepine site of GABA_(A) receptors, including humanGABA_(A) receptors. Without wishing to be bound to any particulartheory, it is believed that the interaction of the compounds of FormulaI with the benzodiazepine site results in the pharmaceutical utility ofthese compounds.

The invention further comprises methods of treating patients in need ofsuch treatment with an amount of a compound of the invention sufficientto alter the symptoms of a CNS disorder. Compounds of the inventionsthat act as agonists at α₂β₃γ₂ and α₃β₃γ₂ receptor subtypes are usefulin treating anxiety disorders such as panic disorder, obsessivecompulsive disorder and generalized anxiety disorder; stress disordersincluding post-traumatic stress, and acute stress disorders. Compoundsof the inventions that act as agonists at α₂β₃γ₂ and α₃β₃γ₂ receptorsubtypes are also useful in treating depressive or bipolar disorders andin treating sleep disorders. Compounds of the invention that act asinverse agonists at the α₅β₃γ₂ receptor subtype or α₁β₂γ₂ and α₅β₃γ₂receptor subtypes are useful in treating cognitive disorders includingthose resulting from Down Syndrome, neurodegenerative diseases such asAlzheimer's disease and Parkinson's disease, and stroke relateddementia. Compounds of the invention that act as agonists at the α₁β₂γ₂receptor subtype are useful in treating convulsive disorders such asepilepsy. Compounds that act as antagonists at the benzodiazepine siteare useful in reversing the effect of benzodiazepine overdose and intreating drug and alcohol addiction.

The diseases and/or disorders that can also be treated using compoundsand compositions according to the invention include:

Depression, e.g. depression, atypical depression, bipolar disorder,depressed phase of bipolar disorder.

Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panicdisorder +/− agoraphobia, social phobia, specific phobia, Post traumaticstress disorder, obsessive compulsive disorder (OCD), dysthymia,adjustment disorders with disturbance of mood and anxiety, separationanxiety disorder, anticipatory anxiety acute stress disorder, adjustmentdisorders, cyclothymia.

Sleep disorders, e.g. sleep disorders including primary insomnia,circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, includingnightmare disorder, sleep terror disorder, sleep disorders secondary todepression and/or anxiety or other mental disorders, substance inducedsleep disorder.

Cognition Impairment, e.g. cognition impairment, Alzheimer's disease,Parkinson's disease, mild cognitive impairment (MCI), age-relatedcognitive decline (ARCD), stroke, traumatic brain injury, AIDSassociated dementia, and dementia associated with depression, anxiety orpsychosis.

Attention Deficit Disorder, e.g. Attention Deficit Disorder (ADD),Attention Deficit Hyperactivity Disorder (ADHD)

The invention also provides pharmaceutical compositions comprising oneor more compounds of the invention together with at least onepharmaceutically acceptable carrier. Pharmaceutical compositions includepackaged pharmaceutical compositions for treating disorders responsiveto GABA_(A) receptor modulation, e.g., treatment of anxiety, depression,sleep disorders or cognitive impairment by GABA_(A) receptor modulation.The packaged pharmaceutical compositions include a container holding atherapeutically effective amount of at least one GABA_(A) receptormodulator as described supra and instructions (e.g., labeling)indicating the contained GABA_(A) receptor ligand is to be used fortreating a disorder responsive to GABA_(A) receptor modulation in thepatient.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds, which comprises administeringan effective amount of a compound of the invention in combination withanother CNS active compound. Such CNS active compounds include, but arenot limited to the following: for anxiety, serotonin receptor (e.g.5-HT_(1A)) agonists and antagonists; for anxiety and depression,neurokinin receptor antagonists or corticotropin releasing factorreceptor (CRF₁) antagonists; for sleep disorders, melatonin receptoragonists; and for neurodegenerative disorders, such as Alzheimer'sdementia, nicotinic agonists, muscarinic agents, acetylcholinesteraseinhibitors and dopamine receptor agonists. Particularly the inventionprovides a method of potentiating the antidepressant activity ofselective serotonin reuptake inhibitors (SSRIs) by administering aneffective amount of a GABA agonist compound of the invention incombination with an SSRI.

Combination administration can be carried out in a fashion analogous tothat disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3)211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le,et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, thediscussion of the use of the GABA_(A) receptor ligand3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinicagonists, muscarinic agonists, and acetylcholinesterase inhibitors, inPCT International publications Nos. WO 99/47142, WO 99/47171, and WO99/47131, respectively. Also see in this regard PCT Internationalpublication No. WO 99/37303 for its discussion of the use of a class ofGABA_(A) receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, incombination with SSRIs.

The present invention also pertains to methods of inhibiting the bindingof benzodiazepine compounds, such as Ro15-1788, to the GABA_(A)receptors which methods involve contacting a compound of the inventionwith cells expressing GABA_(A) receptors, wherein the compound ispresent at a concentration sufficient to inhibit benzodiazepine bindingto GABA_(A) receptors in vitro. This method includes inhibiting thebinding of benzodiazepine compounds to GABA_(A) receptors in vivo, e.g.,in a patient given an amount of a compound of Formula A or Formula Ithat would be sufficient to inhibit the binding of benzodiazepinecompounds to GABA_(A) receptors in vitro. In one embodiment, suchmethods are useful in treating benzodiazepine drug overdose. The amountof a compound that would be sufficient to inhibit the binding of abenzodiazepine compound to the GABA_(A) receptor may be readilydetermined via a GABA_(A) receptor binding assay, such as the assaydescribed in Example 24. The GABA_(A) receptors used to determine invitro binding may be obtained from a variety of sources, for examplefrom preparations of rat cortex or from cells expressing cloned humanGABA_(A) receptors.

The present invention also pertains to methods for altering thesignal-transducing activity, particularly the chloride ion conductanceof GABA_(A) receptors, said method comprising exposing cells expressingsuch receptors to an effective amount of a compound of the invention.This method includes altering the signal-transducing activity ofGABA_(A) receptors in vivo, e.g., in a patient given an amount of acompound of Formula A or Formula I that would be sufficient to alter thesignal-transducing activity of GABA_(A) receptors in vitro. The amountof a compound that would be sufficient to alter the signal-transducingactivity of GABA_(A) receptors may be determined via a GABA_(A) receptorsignal transduction assay, such as the assay described in Example 25.

The GABA_(A) receptor ligands provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to theGABA_(A) receptor.

Labeled derivatives the GABA_(A) receptor ligands provided by thisinvention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

Definitions

For compounds of the present invention that have The compounds of theinvention may have asymmetric centers; this invention includes all ofthe stereoisomers and optical isomers as well as mixtures thereof.

In addition, compounds with carbon-carbon double bonds may occur in Z—and E— forms; all such isomeric forms of the compounds are included inthe invention.

When any variable (e.g. C₁₋₆ alkyl, R¹, R², R⁵, and R⁶) occurs more thanone time in any formula herein, its definition on each occurrence isindependent of its definition at every other occurrence.

As used herein, the terms “alkyl” and “C_(y-x) alkyl” in the presentinvention is meant straight or branched chain alkyl groups of generallyup to 6 or 8 carbon atoms, or for C_(y-x) alkyl the number of carbonatoms specified, for example, C₁₋₆ alkyl indicates straight or branchedchain alkyl groups having from 1 to 6 carbon atoms. Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, and 3-methylpentyl. Preferred C₁₋₈ alkyl groups are methyl,ethyl, propyl, butyl, pentyl and cyclopentyl.

As used herein, “alkanoyl” refers to an alkyl group as defined aboveattached through a carbonyl bridge. Examples include acetyl, propionyl,and butyryl.

The term “alkoxy” represents an alkyl group, as described above,attached through an oxygen bridge, such as methoxy, ethoxy, propoxy andisopropoxy.

The term “alkenyl” is intended to include hydrocarbon chains of either astraight or branched configuration comprising one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl and propenyl.

The term “alkynyl” is intended to include hydrocarbon chains of either astraight or branched configuration comprising one or more triplecarbon-carbon bonds which may occur in any stable point along the chain,such as ethynyl and propynyl.

As used herein, “carbocyclic group” refers to aromatic carbocyclic ringsystems and to cycloalkyl ring systems that have one or more double ortriple bonds.

The term “aryl” is used to indicate aromatic groups that contain onlycarbon atoms in the ring structure. Thus, the term “aryl” refers to anaromatic hydrocarbon ring system containing at least one aromatic ring.The aromatic ring may optionally be fused or otherwise attached to otheraromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examplesof aryl groups are, for example, phenyl, naphthyl,1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred examplesof aryl groups include phenyl and naphthyl. The aryl groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. Thus, such aryl groups are optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono- or di-(C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl,.

The term “cycloalkyl” as used herein refers to saturated ring groups,having the specified number of carbon atoms, e.g., C₃-C₇ cycloalkyl,such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certainsituations, the cycloalkyl group will contain one or more double ortriple bonds and may be substituted with one or more substituents suchas C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono- or di-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, aryl and heteroaryl. Cycloalkyl groupsherein that lack any unsaturation are referred to as saturatedcycloalkyl groups while cycloalkyl groups that contain at least onedouble or triple bond but are not aromatic are referred to as eitherunsaturated or partially unsaturated.

The term “cycloalkylalkyl” refers to cycloalkyl groups as defined aboveattached to an alkyl group. Generally, the cycloalkyl group will containfrom 3-7 carbon atoms and the alkyl portion will contain from 1-8, morepreferably, 1-6, carbon atoms. These cycloalkylalkyl groups areidentified herein as C₃-C₇ cycloalkyl(C₁-C₆)alkyl groups. Examples ofsuch groups are cyclopropylmethyl, cyclohexylmethyl, andcyclohexylmethyl.

The term “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. Preferredhaloalkyl groups are halo(C₁-C₆)alkyl groups; particularly preferred aretrifluoromethyl, perfluoropropyl, and difluoromethyl.

By “haloalkoxy” as used herein is meant represents a haloalkyl group, asdefined above, attached through an oxygen bridge to a parent group.Preferred haloalkoxy groups are halo(C₁-C₆)alkoxy groups. Examples ofhaloalkoxy groups are trifluoromethoxy, 2,2-difluoroethoxy,2,2,3-trifluoropropoxy and perfluoroisopropoxy.

As used herein, the group “VY” represents V and Y connected by a singleor double bond. Similarly, the groups “UY” and “VY” represent single ordouble bonds connecting U and Y and V and Y respectively. In specificembodiments, where these groups are double bonds, they give rise toaromatic groups.

The term “heterocycloalkanone” refers to 4-, 5-, 6- and 7-membered ringsystems having at least one hetero atom selected from oxygen, nitrogen,and sulfur and also having at least one oxo group, i.e., the ringcontains a carbonyl group. Such heterocycloalkanone groups areoptionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen,amino, mono- or di(C₁-C₆)alkylamino, and the like. Examples include

As used herein, the terms “heterocyclic group” or “heterocycloalkyl” areintended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to10-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 hetero atoms independently selected from N, O andS and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurhetero atoms may optionally be oxidized. The term “heteroaryl” is usedto specifically indicate aromatic heterocyclic groups.

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the totalnumber of S and O atoms in the heterocycle is not more than 1. As usedherein, the term “aromatic heterocyclic system” is intended to mean astable 5-to 7-membered monocyclic or bicyclic or 7- to 10-memberedbicyclic heterocyclic aromatic ring which consists of carbon atoms andfrom 1 to 4 hetero atoms independently selected from N, O and S. It ispreferred that the total number of S and O atoms in the aromaticheterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benoztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Where an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl issubstituted with oxo, the resulting groups will have an oxygen atomconnected to a ring within the system by a double bond. Examples of suchoxo substiuted systems include 2-oxo-1,2-dihydro-pyridin-3-yl and2-oxo-1,2-dihydro-pyridin-4-yl groups. Such groups have the formulas

These groups may be substituted on any of the ring carbon atoms or thering nitrogen, with various substituents as specified herein.

The term “halogen” indicates fluorine, chlorine, bromine, and iodine.

Non-toxic “pharmaceutically acceptable salts” include, but are notlimited to salts with inorganic acids such as hydrochloride, sulfate,phosphate, diphosphate, hydrobromide, and nitrite or salts with anorganic acid such as malate, maleate, fumarate, tartrate, succinate,citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate,2-hydroxyethylsulfonate, salicylate and stearate. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. The presentinvention also encompasses the prodrugs of the compounds of Formula I.

Pharmaceutical Preparations

Those skilled in the art will recognize various synthetic methodologiesthat may be employed to prepare non-toxic pharmaceutically acceptableprodrugs of the compounds encompassed by Formula I. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable solvents that may be used to prepare solvates of thecompounds of the invention, such as water, ethanol, mineral oil,vegetable oil, and dimethylsulfoxide.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includessubcutaneous injections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions so that theanimal takes in an appropriate quantity of the composition along withits diet. It will also be convenient to present the composition as apremix for addition to the feed or drinking water.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof anxiety, depression, or cognitive impairment a dosage regimen of 1 or2 times daily is particularly preferred. For the treatment of sleepdisorders a single dose that rapidly reaches effective concentrations isdesirable.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lifes. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat peripheral disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lifes of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Preparation of Compounds

A general illustration of the preparation of compounds of Formula I inthe present invention is given in Schemes 1-12. In the reaction schemesand discussions that follow, unless otherwise indicated, k, R^(A), R¹,R², R³, R⁴, R⁵, R⁶ are as defined above. Within the schemes and tablesthat follow, Ar is intended to represent Q—(CH₂)_(n)—W—(CH₂)_(m)—Z asdefined in Formula I or a suitably protected form thereof. When aprotecting group is required, an optional deprotection step may beemployed. Suitable protecting groups and methodology for protection anddeprotection such as those described in Protecting Groups in OrganicSynthesis by T. Greene are well known and appreciated in the art.Compounds and intermediates requiring protection/deprotection will bereadily apparent to those skilled in the art.

In Scheme 1 step 1, p-nitrophenethylamine is alkylated with tert-butylbromo acetate to form compound (2). In general, excessp-nitrophenethylamine is used in this reaction to minimizebis-alkylation. In step 2, the secondary amine in compound (2) iscoupled with BOC-protected 3-aminopropanoic acid to form compound (3).This coupling may be efficiently accomplished by treating a mixture ofcompound (2) in pyridine with N-Boc 3-aminopropanoic with a couplingagent such as EDCI with stirring at ambient temperature. In step 3, thetert-butyl ester in compound (3) is cleaved under basic conditions toform the carboxylic acid (4). Compound (4) is reacted with dimethylacetylene dicarboxylate in the presence of acetic anyhydride in step 4to form the pyrrole (5). Pyrrole (5) is sequentually deprotected usinghydrogen chloride in step 5 to expose the primary amine in compound (6)and cyclized in the presence of base to form lactam (7). In step 6,lactam (7) is converted to the thiolactam (8) by reaction underappropriate sulfur transfer conditions such as heating with P₄S₁₀ inpyridine. In steps 7 and 8, thiolactam (8) is alkylated with methyliodide in acetone to form the methylsulfanyl compound (9) which isreacted with aminoacetaldehyde dimethyl acetal in methanol to formcompound (10). Cyclization of the dimethyl acetal derivative (10) isaccomplished in step 9 by heating (10) with concentrated hydrochloricacid in methanol to form compound (11). Removal of the p-nitrophenethylprotecting group is accomplished in step 10 by treatment of (11) withsodium hydride in the presence of di-tert-butyl dicarbonate indimethylformamide. Quenching of excess sodium hydride with acetic acidfollowed by hydrolysis of the BOC group from the pyrrole nitrogen usingaqueous potassium bicarbonate provides the desired deprotected material(12). As indicated by step 11 in Scheme 1, ester (12) serves as aversatile acylating agent for a variety of aluminum complexes of aryland heteroaryl amines to form the corresponding amides (13).

Another procedure for forming amide derivatives (13) is provided inExample 2a and involves hydrolysis of ester (12) by heating in thepresence of 48% hydrobromic acid. The resulting carboxylic acid is thenreacted with various aryl amines in the presence of an appropriatecoupling reagent such asO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate. Alternatively, the carboxylic acid may be convertedto the mixed anhydride by reaction with ethyl or isobutyl chloroformatein the presence of triethylamine. The resulting mixed anhydride is thenreacted with aryl amines.

Compounds of Formula II where R⁵ or R⁶ is methyl are formed asillustrated in Scheme 1 by reaction of compound (2) with 3-aminobutyricacid in step 2. Optically pure or optically enriched material isobtained by separation of advanced intermediates on a suitable chiralHPLC column such as Chiralpak AD. For material resolved by this method,the absolute stereochemistry is correlated to a X-ray crystal structureof a chiral amide derivative. Alternatively, optically pure3-aminobutyric acid may be employed in step 2. Compounds of Formula IIwherein both R⁵ and R⁶ are methyl are obtained as illustrated in Scheme1 by use of 3-amino-3-methylbutyric acid in step 2.

Compounds of Formula II wherein R³ is methyl may be formed asillustrated by Scheme 1 by employing 2-aminopropionaldehyde dimethylacetal in step 8.

Those skilled in the art will realize that the synthetic transformationsdescribed by Scheme 1 may be accomplished using a variety of alternatereagents and reaction conditions. Further, it is readily apparent thatadditional compounds within the scope of Formula II but not specificallydescribed within the experimental section may be prepared in analogousfashion.

Scheme 2 reveals a method for converting known ketone (14) (U.S. Pat.No. 5,723,462, col.23-31 is hereby incorporated by reference for itsteachings regarding the synthesis of such ketones) to compounds ofFormula III with R³ as methyl. Step 1 describes formation of theBOC-protected derivative (15). Typically this transformation is carriedout by treating pyrrole (14) with di-tert-butyl dicarbonate in asuitable solvent such as dichloromethane or 1,4-dioxane at temperaturesranging from 0° C. to ambient temperature in the presence of an organicbase such as triethylamine. Additives such as4-N,N-dimethylaminopyridine may be used to facilitate thistransformation. In step 2, the BOC-protected material (15) isefficiently converted to silyl enol ether (16) by treatment with amixture of trimethylsilyl chloride, sodium iodide and triethylamine atambient temperature. Lewis acid-facilitated 1,4-addition is accomplishedin step 3 by treatment with excess methyl vinyl ketone at 0° C. in thepresence of zinc chloride-alumina to yield the diketone (17). Treatmentof the diketone (17) with ammonium acetate at elevated temperature instep 4 provides the desired methyl-substituted pyridyl derivative (18)which is aminated in step 5 using amination conditions previouslydescribed for Scheme 1.

Scheme 3 shows a method for converting known ketone (14) [U.S. Pat. No.5,723,462] to compounds of Formula III with R³ as hydrogen. In step 1,pyridine ring formation is accomplished by treatment of ketone (14) with3-aminoacrolein (R═H) and catalytic ammonium acetate in triethylamine atelevated temperature. Conversion of (14) to (20) can also beaccomplished by heating (14) in triethylamine with3-dimethylaminoacrolein in the presence of excess ammonium acetate. If3-amino-2-methylacrolein (R═CH₃) is used in step 1, a 3-methylpyridinering is formed. Amination is accomplished in step 2 as previouslydescribed.

Those skilled in the art will recognize that the reactions described inScheme 3 may also be applied to synthesize compounds of Formula IIIwherein k=1 by starting with the appropriate known ketone.

Scheme 4 outlines conditions for conversion of ketone (15) to compoundsof Formula IV. In step 1, ketone (15) is reacted withtris(dimethylamino)methane with heating in a sealed tube to affordcompound (22). In step 2, compound (22) undergoes reaction withformamidine acetate in ethanol at 120° C. to yield the pyrimidinederivative (23). As shown in step 3, compound (23) serves as a versatileintermediate for reaction with aluminum complexes of a variety of arylamines under conditions previously described.

Scheme 5 describes a method for producing compounds of Formula IVwherein R⁴ is methyl. Reaction of compound (16) from Scheme 2 withacetyl chloride in the presence of catalytic sodium iodide and asuitable Lewis acid such as bismuth trichloride gives diketone (25).Subsequent reaction with formamidine acetate as per Scheme 4, providesmethyl pyrimidine (26) which is aminated in step 3 as previouslydescribed.

Scheme 6 provides a means of obtaining compounds of Formula V. In step1, compound (22) from Scheme 4 is reacted with methylhydrazine(R^(A)═CH₃) in ethanol at 120° C. to obtain approximately a 3:1 mixtureof compounds (28) and (29). The structure of compound (28) is assignedbased on X-ray crystal analysis. After separation by chromatography onsilica gel, compound (28) is converted to amide derivatives in step 2 aspreviously described. Compound (29) may likewise be reacted. Reaction of(22) with hydrazine acetate as shown in step la provides a pyrazole ringwith a free NH. To improve the handling characteristics of thismaterial, it is BOC-protected by means of reaction with di-tert-butyldicarbonate in the presence of triethylamine to give compound (31).Compound (31) can be converted to amide derivatives (32) as shown instep 2a using previously described conditions.

Compounds of Formula V, wherein R^(A) is a substituted aminoethylsubstituent, may be prepared as shown in step 3. Compound (28)(R^(A)═CH₂CH₂OH), which is prepared as shown in step 1 by the reactionof (22) with 2-hydroxyethylhydrazine, is converted to the correspondingmesylate using standard conditions, such as methanesulfonyl chloride inthe presence of pyridine. The mesylate is then displaced with variousamines in the presence of K₂CO₃ and CH₃CN at elevated temperature toproduce compounds (6A). Amide derivatives (6B) are prepared as shown insteps 2b and 2c using previously described conditions.

Compounds of Formula V may also be prepared by first introducing theamide functionality. Thus, compound (14) is first aminated as previouslydescribed [U.S. Pat. No. 5,723,462] and the amide derivatives convertedto enaminone derivatives (6C) using conditions analogous to those forthe preparation of (22) (Scheme 4). Compound (6C) is converted tovarious ethyl pyrazole derivatives as shown in steps 1b, 3a, and 3busing previously described methods. Those skilled in the art willrecognize that compounds of Formula V containing a variety of R^(A)groups, such as alkyl, alkoxy ethyl, and variously substitutedaminoethyl groups, may be prepared using methods analogous to thosedepicted in Scheme 6.

Those skilled in the art will also recognize that compounds of FormulaV, wherein R⁴═CH₃, may be prepared from compound (25) (Scheme 5) usingconditions analogous to those shown in Scheme 6.

Scheme 7 illustrates the synthesis of isoxazole derivatives of FormulaVI. In step 1, compound (22) from Scheme 4 is reacted with hydroxylaminehydrochloride in ethanol at 100° C. to provide isoxazole (33). Analogousreaction of diketone (25) with hydroxylamine hydrochloride affords themethyl isoxazole (35). Amination of (33) and (35) is accomplished insteps 2 and 2a using previously described

The synthesis of compounds of Formula VII and Formula VIII is outlinedin Scheme 8. In Scheme 8 step 1, ketone (15) from Scheme 2 is brominatedwith a suitable brominating agent such as1,3-dibromo-4,4-dimethylhydantoin. The resulting bromoketone (37) isreacted with various amidines in step 2 to give the correspondingimidazoles (38). Typically, the amidine hydrochloride is used in thepresence of excess base in 1,4-dioxane as solvent. Alternatively,bromoketone (37) can be reacted with thioamides to form thiazolederivatives (40). The esters (38) and (40) react to form amides as insteps 3 and 3a as previously described. Examples in the presentinvention of Formula VII and VIII with k=1 are formed using entirelyanalogous procedures.

Scheme 9 illustrates the synthesis of fused imidazo derivatives (46).Step 1 involves a regioselective Schmidt type rearrangement of theketone (42). The resulting amide (43) is converted to the thioamide (44)in Step 2. Thioamide (44) is efficiently converted to amidine (44) inthe presence of mercury (II) acetate. Treatment of (44) withconcentrated hydrochloric acid in Step 4 followed by amination of theester in Step 5 provides the desired amide (46).

Scheme 10 illustrates the synthesis of 7H-pyrrolo [2,3c][1,5]naphthyridine derivatives (55). Step 1 involves reaction ofnitropyridine derivative (47) with1-chloromethane-sulfonyl-4-methyl-benzene in the presence of strongbase. In Step 2, (48) is alkylated with ethyl bromoacetate in thepresence of base. Catalytic hydrogenation of (49) in Step 3 efficientlyprovides 3-aminopyridine derivative (50) which is subsequently protectedin Step 4 using carbobenzyloxy chloride to provide (51). Heating (51)with strong base in Step 5 yields the acrylic acid derivative (52).Intermediate (52) is converted the pyrrole (53) in Step 6 usingtosylmethyl isocyamide and base. Reaction of (53) with phosphorousoxychloride in the presence of DMF provides cyclized produce (54). InStep 8, ester derivative (54) is conveniently converted to amide (55) byreaction with aryl and heteroaryl amines in the presence of trimethylaluminum. Preparation of 7H-pyrrolo [2,3c] [1,5] naphthyridinederivatives according to Scheme 10 is further illustrated by Example21b.

Scheme 11 illustrates the synthesis of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives (62). InStep 1, acrylic acid derivative (56) is converted the pyrrole (57) inusing tosylmethyl isocyamide and base. Step 2 involves reaction ofpyrrole (57) with phosphorous oxychloride in the presence of DMF toobtain the aldehyde (58). Catalytic hydrogenation of nitrile (58)results in cyclized product (59) which is converted in Step 4 to amide(60) using trimethyl aluminum in the presence of an appropriate aryl orheteroaryl amine. In optional Steps 4′ and 5′, (59) is converted toN-alkylated product (61) via reductive amination and subsequentlyreacted to form amide (62). Preparation of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives accordingto Scheme 11 is further illustrated by Examples 21d and 21e.

Scheme 12 illustrates the synthesis of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives(74). In Step 1, 2-methylpyridine (63) is oxidized to aldehyde (64) inthe presence of selenium dioxide. The aldehyde group in (64) isprotected as the dimethyl ketal (65) in Step 2. Reduction of (64) inStep 3 using lithium aluminum hydride followed by oxidation to aldehydein Step 4 using manganese dioxide provides aldehyde (67). Reductiveamination of (67) in Step 5 with N-benzyl methyl amine provides (68)which is deprotected under acidic conditions in Step 6 to aldehyde (69).In Step 7, aldehyde (69) is reacted with triethylphosphoro-acetate andpotassium bis(trimethylsilyl) amide to form acrylic acid derivative(70). In Step 8, reaction of (70) with tosylmethyl isocyamide and baseprovides pyrrole (71). Reaction of (71) with phosphorous oxychloride andDMF in Step 9 provides aldehyde (72) which is subsequently hydrogenatedin Step 10 to provide cyclized product (73). Ester (73) is convenientlyconverted to amide (74) in the presence of trimethyl aluminum and anappropriate aryl or heteroaryl amine. Preparation of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivativesaccording to Scheme 12 is further illustrated by Example 21f.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them.

EXAMPLES Example 1 Preparation of5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester

Step 1:

To a solution of p-nitro phenethylamine (45.3 mmol) in 75 mL water isadded enough 30% NaOH in water to achieve a pH of 12. The water layer isextracted with dichloromethane. The organic layers are collected, driedover Na₂SO₄, and evaporated in vacuo yielding 7.4 g yellow brown oil(98%). To a partialy dissolved mixture of free base (44.58 mmol) inether bromoacetic acid t-butyl ester (22.29 mmol) is slowly added over15 min. Using an overhead stirring apparatus, the resulting mixture isstirred for 3½ days under a nitrogen atmosphere. Water is added to thereaction mixture, and the ether layer is washed 3 times with water andonce with brine. The water layers are collected and back-extracted witha 50/50 ether/ethyl acetate mix. All the organic layers are collected,dried over Na₂SO₄, and evaporated in vacuo. The dark orange solid ischromatographed using hexane 3:ethyl acetate 1 as mobile phase to yield3.48 g yellow solid (56%): ¹H NMR (CDCl₃) 1.42 (s, 9H), 2.90 (s, 4H),3.29 (s, 2H), 7.35 (d, 2H), 8.13 (d, 2H); LRMS calcd 280.33, found [M+H]281.1.

Step 2:

To a mixture of 2-(4-Nitro-phenyl)-ethylamino-acetic acid tert-butylester in 1 mL pyridine is added N-BOC β-alanine (0.178 mmol), and EDCI(0.214 mmol). After stirring at room temperature for 3½ hours, thepyridine is evaporated at reduced pressure. The remaining oil is takenup in ethyl acetate and washed with dilute hydrochloric acid. Theorganic layers are combined, dried over Na₂SO₄, and evaporated in vacuoyielding(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-α-amino-aceticacid tert-butyl ester, 78 mg yellow oil: ¹H NMR (CD₃OD) 1.45 (d, 9H),1.50 (d, 9 h), 2.46-2.48 (m, 2H), 2.98-3.08 (m, 2H), 3.27-3.35 (m, 2H),3.62-3.75 (m, 2H), [4.03, 4.11](s, 2H), 7.56-7.59 (m, 2H), 8.20-8.23 (m,2H); LRMS calcd 451.52, found [M] 451.2.

Step 3:

To a mixture of{(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-aceticacid tert-butyl ester (2.5 mmol) in 11 mL THF is 22 mL water added,followed by NaOH (17.5 mmol). After heating at 60° C. for 5½ hours it isquenched with acetic acid (20 mmol). It is placed in the refrigeratorfor 2% days. The THF is evaporated off, and the remaining water isextracted several times with EtOAc. The organic layers are combined,dried over Na₂SO₄ and evaporated in vacuo yielding{(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-aceticacid, 983 mg, as a dark yellow/brown oil/foam (99%): ¹H NMR (CD₃OD) 1.40(d, 9H), 2.44-2.45 (m, 2H), [2.98, 3.03](t, 2H), 3.22-3.30 (m, 2H),[3.60, 3.65](t, 2H), 4.06 (s, 2H), [7.52, 7.54](d, 2h), 8.16 (t, 2H);LRMS calcd 395.42, found [M−H] 394.0.

Step 4:

To a mixture of{(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-aceticacid (0.253 mmol) in 1 ml acetic anhydride is dimethyl acetylenedicarboxylate (0.278 mmol) added. After stirring at 85° C. for 4½ hoursthe solvent is evaporated in vacuo. The dark brown oil ischromatographed using ethyl acetate 2:Hexane 3 as a mobile phase toyield2-(2-tert-Butoxycarbonylamino-ethyl)-1-[2-(4-nitro-phenyl)-ethyl]-1H-pyrrole-3,4-dicarboxylicacid dimethyl ester, 79 mg, as a yellow oil (66%): ¹H NMR (CD₃OD) 1.50(s, 9H), 2.84 (t, 2H), 3.14-3.34 (m, 4H), 3.77 (s, 3H), 3.82 (s, 3H),4.33 (t, 2H), 6.74 (t, 1H), 7.29 (s, 1H), 7.44 (d, 2H), 8.16 (d, 2H)LRMS calcd 475.50, found [M] 475.1.

Step 5:

A solution of2-(2-tert-Butoxycarbonylamino-ethyl)-1-[2-(4-nitro-phenyl)-ethyl]-1H-pyrrole-3,4-dicarboxylicacid dimethyl ester (0.292 mmol) in 10 HCl/ethyl acetate is stirred atRT for % hour. The solvent is evaporated in vacuo and placed on the highvacuum pump for several hours yielding 139 mg white solid ¹H NMR (CD₃OD)2.92-2.94 (m, 2H), 2.97-2.99 (m, 2H), 3.20 (t, 3H), 3.75 (s, 3H), 3.79(s, 3H), 4.26 (t, 2H), 7.33 (d, 3H), 8.15 (d, 2H). LRMS calcd 375.38,found [M+H] 376.2) which is stirred in 7 mL THF with triethylamine(1.168 mmol) at 60° C. for 16 hours. The solvent is evaporated in vacuoand chromatographed using ethyl acetate 9:MeOH 1 as mobile phase toyield1-[2-(4-Nitro-phenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylicacid methyl ester, 73 mg, as a white solid (73%): ¹H NMR (CD₃OD) 2.47(t, 2H), 3.16 (t, 2H), 3.23-3.33 (m, 2H), 3.74 (s, 3H), 4.23 (t, 2H),7.30 (t, 3H), 8.11 (d, 2H); LRMS calcd 343.33, found [M+H] 344.2.

Step 6:

In a round bottom flask under N₂ atm. are the1-[2-(4-Nitro-phenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid methyl ester (48.64 mmol), P₄S₁₀ (24.32 mmol) and 240 mL pyridinecombined and heated at 65° C. for 8 hours. After cooling to RT it ispoured over ˜600 mL ice and stirred for 2 hours. The yellow solid isfiltered off, washed (2×) with water and dried on the high vacuum for 18h to yield1-[2-(4-Nitro-phenyl)-ethyl]-4-thioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylicacid methyl ester, 10.24 g, as a yellow solid (65%): ¹H NMR (CD₃OD) 2.43(t, 2H), 3.16 (t, 2H), 3.28-3.33 (m, 2H), 3.75 (s, 3H), 4.21 (t, 2H),7.16 (s, 1H), 7.30 (d, 2H), 8.13 (d, 2H); LRMS calcd 359.41, found [M+H]360.2.

Step 7:

To a solution of1-[2-(4-Nitro-phenyl)-ethyl]-4-thioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2c]pyridine-3-carboxylicacid methyl ester (28.16 mmol) in 130 mL acetone is MeI (56.32 mmol) andK₂CO₃ (84.48 mmol) added. The reaction mixture is stirred at RT for 2½hours whereby the acetone is evaporated in vacuo. The remaining oil istaken up in Dichloromethane and washed two times with water. The organicsolvents are collected, dried over Na₂SO₄ and evaporated in vacuo toyield4-Methylsulfanyl-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid methyl ester, 9.46 g, as a yellow foam (90%); ¹H NMR (CD₃OD)2.34-2.39 (m, 5H), 3.21 (t, 2H), 3.56 (t, 2H), 3.80 (s, 3H), 4.29 (t,2H), 7.32-7.38 (m, 3H), 8.17 (d, 2H); LRMS calcd 373.43, found [M+H]374.2.

Step 8:

In a round bottom flask are4-Methylsulfanyl-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylicacid methyl ester (25.33 mmol), amino acetaldhyde dimethyl acetal (63.32mmol) and 125 mL MeOH combined (a part “oiled-out” that later went intosolution) and stirred at RT for 20 hours. The solvent is evaporated invacuo yielding4-(2,2-Dimethoxy-ethylamino)-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid methyl ester, 11.56 g, as a yellow oil/solid that is used withoutpurification.

Step 9:

To a solution of4-(2,2-Dimethoxy-ethylamino)-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid methyl ester (25.33 mmol) in 125 mL MeOH is 10 mL HCl conc. added.It is heated at 63° C. for 15 hours. Since the reaction is not completeanother 5 mL HCl conc. is added, and it is heated again at 63° C. for 10hours. The solvent is evaporated in vacuo, and the remaining oil isdissolved in MeOH whereby K₂CO₃ (1.2 eq.) is added. After stirred at RTfor 1 h the solid is filtered off, washed with MeOH and the filtrate isevaporated in vacuo yielding a yellow solid that is protonated. Theprotonated product is stirred in Dichloromethane and saturated NaCO₃sol. until everything dissolved. The two layers are separated and thewater layer is extracted two times with dichloromethane. The organiclayers are collected, dried and evaporated in vacuo yielding a free basewhich is triturated in ethyl acetate yielding6-[2-(4-Nitro-phenyl)-ethyl]-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylicacid methyl ester, 9.11 g, as a yellow solid (77%): ¹H NMR (CD₃OD) 2.76(t, 2H), 3.18 (t, 2H), 3.78 (s, 3H), 4.07 (t, 2H), 4.28 (t, 2H), 6.94(s, 1H), 7.01 (s, 1H), 7.31 (d, 3H), 8.10 (d, 2H); LRMS calcd 366.38,found [M+H] 367.2.

Step 10:

To a solution of6-[2-(4-Nitro-phenyl)-ethyl]-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylicacid methyl ester (19.67 mmol) in 100 mL DMF is treated with sodiumhydride (60%, 1.97 g, 49.18 mmol) portion wise. The reaction is completein about 2 h at 20° C. Chloroform is added and the reaction mixture iscooled to 5° C. before the dropwise addition of acetic acid (3.15 mL,55.08 mmol) until pH of 1-3. A saturated solution of aqueous KHCO3 (150mL) is added, stirred and separated. The separated organic phase iswashed with water twice. The filtrate is concentrated directly. Most ofthe DMF is removed by high vacuum to give a brown wet solid. The wetsolid is cooled to room temp. Ether is added, stirred, and filtered togive a brown solid which is dried in air overnight to give5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester,9.11 g, (77%): ¹H NMR (CD₃OD) 3.05 (t, 2H), 3.86 (s, 3H), 4.25 (t, 2H),6.97 (s, 1H), 7.05 (s, 1H), 7.40 (s, 1H); LRMS calcd 217.23, found [M−H]216.1.

Example 2 Preparation of5,6-Dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid(2-fluoro-phenyl)-amide

To a solution of 2-fluoroaniline (84 uL, 0.829 mmol) in 2 mLdichloromethane at room temperature is added a 2M solution oftrimethylaluminum in toluene (414 uL, 0.829 mmol) and the reaction isstirred at room temperature for 0.5 h. This solution is then syringedinto the neat give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylicacid methyl ester (90 mg, 0.415 mmol) and stirred at reflux for 10 h.The reaction mixture is diluted with dichloromethane and poured ontowater (30 mL). The whole mixture is filtered through celite and thenseparated. The aqueous phase is washed with dichloromethane and thecombined organics are dried (Na2SO4) and concentrated in vacuo. Theresidue is purified by Flash-40 chromatography (EtOAc) to afford theproduct, 5,6-Dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid(2-fluoro-phenyl)-amide, 63 mg, as an glassy oil (48%): ¹H NMR (DMSO)3.25 (t, 2H), 4.44 (t, 2H), 7.23-7.42 (m, 4H), 7.57-7.63 (m, 2H), 7.96(s, 1H); LRMS calcd 296.30, found (M−H) 295.0.

Example 2a 5,6-Dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidhydrobromide

A solution of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidmethyl ester (516 mg) and 48% hydrobromic acid (5 mL) is heated at 600for 60 hours. The mixture is cooled to room temperature and concentratedin vacuo. The residue is slurried with diethyl ether and the ether isdecanted off. This is repeated until no more color is visible in theether layer. The remaining solid is dried in vacuo to give5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide,350 mg, brown solid: ¹H NMR(DMSO-d₆) 3.17 (2H, t), 4.40 (2H, t), 7.35(1H, d), 7.57 (1H, d), 7.63 (1H, s) 12.34 (1H, s), 12.45 (1H, s).

Example 2b 5,6-Dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid(4-fluorophenyl)amide

A mixture of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidhydrobromide (58 mg),O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (181 mg), triethylamine (0.07 mL), 4-fluoroaniline(30 mg), and N,N-dimethylformamide (4 mL) is heated at 400 for 18 hours.The mixture is cooled to room temperature, treated with water (15 mL),and extracted with ethyl acetate (3×50 mL). The combined organic layersare washed with water (2×15 mL) and brine (1×15 mL), dried overmagnesium sulfate, and concentrated in vacuo. The residue is purified bypreparative thin layer chromatography on silica gel, eluting with 5%methanol in dichloromethane, to give5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid(4-fluorophenyl)amide, pale brown solid, 18 mg: LRMS calcd 296.30, found[M+H] 297.2.

Example 2c4-Methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic methylester

The title compound is prepared following the procedure outlined inExample 1 starting with 3-aminobutyric acid: Electrospray MS m/z 232[M+1]; ¹H NMR (DMSO-d6, 300 MHz) δ11.62 (s, 1H) 7 .38 (s, 1H), 7.08 (s,1H), 6.81 (s, 1H), 4.43 (m, 1H), 3.68 (s, 3H), 3.05 (dd, 1H), 2.67 (dd,1H), 1.38 (d, 3H).

Example 2d4,4-Dimethyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylicmethyl ester

The title compound is prepared following the procedure outlined inExample 1 starting with 3-amino-3-methylbutyric acid: Electrospray MSm/z 246 [M+1]; ¹H NMR (DMSO-d6, 300 MHz) δ11.70 (s, 1H), 7.39 (s, 1H),7.18 (s, 1H), 6.82 (s, 1H), 3.68 (s, 3H), 2.85 (s, 2H), 1.40 (s, 6H)

Example 2e4-Methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidphenyl amide

A mixture of4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidhydrobromide (25 mg), aniline (12 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg),1,4-dioxane (1.5 mL), and water (1.5 mL) is stirred at room temperaturefor 4 days. 0.5N sodium hydroxide solution (3 mL) is added and themixture is extracted with dichloromethane (3×50 mL). The combinedorganic layers are washed with brine (1×10 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified bypreparative thin layer chromatography on silica gel, eluting with 5%methanol in dichloromethane, to give4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidphenyl amide, cream solid, 7 mg: LRMS calcd 292.34, found [M+H] 293.2.

Example 3 4-Methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylicacid (2-fluoro-4-isopropoxyphenyl)amide

Ethyl chloroformate (66 μL) is added dropwise to an ice-cold mixture of4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acidhydrobromide (192 mg), triethylamine (0.33 mL), andN,N-dimethylformamide (5 mL). The mixture is stirred at 0° for 1 hourthen at room temperature for 30 minutes. 2-Fluoro-4-isopropoxyaniline(66 mg) is added and the mixture is stirred at room temperature for 18hours. The mixture is diluted with ethyl acetate (50 mL) then treatedwith water (25 mL), and extracted with ethyl acetate (3×50 mL). Thecombined organic layers are washed with water (2×20 mL) and brine (1×20mL), dried over magnesium sulfate, and concentrated in vacuo. Theresidue is purified by preparative thin layer chromatography on silicagel, eluting with diethyl ether, to give a brown solid. This is treatedwith ethanol (2 mL) and saturated aqueous potassium carbonate solution(1 mL) and the mixture is heated at 600 for 30 minutes. The mixture iscooled to room temperature and diluted with water (3 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers are washedwith brine (1×10 mL), dried over magnesium sulfate, and concentrated invacuo. The oily residue is purified by preparative thin layerchromatography on silica gel, eluting with 10% methanol indichloromethane, to give4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid(2-fluoro-4-isopropoxyphenyl)amide, pale yellow solid, 10 mg: LRMS calcd368.40, found [M+H] 369.2.

Example 4

Using methods as generally shown in Scheme 1 and further illustrated inExamples 1, 2-2e, and 3 the compounds shown in Table 1 were synthesized.

The column headings used to indicate substituents groups in Table1-Table 8, e.g. R1, R2, Ar, are intended for use only in the Table inwhich they appear.

TABLE 1

Cpd # Name R3 R4 R5 R6 k Ar Spectral Data 1. 5,6-Dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-chloro- phenyl)-amide HH H H 1

¹H NMR (DMSO) 3.24 (t, 2H), 4.44 (t, 2H), 7.37 (s, 1H), 7.45 (d, 2H),7.65 (s, 1H), 7.82 (d, 2H), 8.01 (m, 1H) LRMS calcd 312.76 found (M−H)311.0 2. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acidphenylamide H H H H 1

¹H NMR (DMSO) 3.24 (t, 2H), 4.44 (t, 2H), 7.14 (t, 1H), 7.37-7.42 (m,3H), 7.65 (s, 1H), 7.77 (d, 2H), 8.00 (s, 1H) LRMS calcd 278.31 found(M−H) 277.0 3. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylicacid (3-fluoro-4- methoxy-phenyl)-amide H H H H 1

¹H NMR (DMSO) 3.23 (t, 2H), 3.84 (s, 3H), 4.44 (t, 2H), 7.19 (t, 1H),7.37-7.44 (m, 2H), 7.64 (s, 1H), 7.79 (d, 1H), 7.95 (s, 1H) LRMS calcd326.33 found (M−H) 325.2 4. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid 2-fluoro-benzylamide H H H H 1

¹H NMR (DMSO) 3.21 (t, 2H), 4.41 (t, 2H), [4.52, 4.58] (d, 2H),7.17-7.24 (m, 2H), 7.31-7.41 (m, 3H), 7.60 (s, 1H), 7.78 (s, 1H) LRMScalcd 310.33 found [M−H] 309.0 5. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-methoxy-phenyl)-amide H H H H 1

¹H NMR (DMSO) 3.19 (t, 2H), 3.72 (s, 3H), 4.39 (t, 2H), 6.92 (d, 2H),7.31 (s, 1H), 7.60 (d, 3H), 7.92 (s, 1H) LRMS calcd 308.34 found [M+H]309.0 6. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acidbenzylamide H H H H 1

¹H NMR (DMSO) 3.18 (t, 2H), 4.37 (t, 2H), 4.49 (d, 2H), 7.22-7.24 (m,1H), 7.27-7.33 (m, 5H), 7.56 (s, 1H), 7.72 (s, 1H), 9.03 (m, 1H) LRMScalcd 292.34 found [M+H] 293.4 7. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2,4-difluoro- phenyl)-amide H H H H 1

¹H NMR (CD3OD) 3.28-3.31 (m, 2H), 4.7 (t, 2H), 6.95-7.04 (m, 1H),7.05-7.09 (m, 1H), 7.31 (s, 1H), 7.43 (s, 1H), 7.69-7.74 (m, 1H), 7.79(s, 1H), 9.80 (s, 1H) LRMS calcd found [M+ ] 8. 5,6-Dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid p-tolylamide H H H H 1

¹H NMR (CD3OD) 2.30 (s, 3H), 3.10 (t, 2H), 4.24 (t, 2H), 7.03-7.04 (m,2H), 7.14 (d, 2H), 7.42 (s, 1H), 7.69 (d, 2H) LRMS calcd 292.34 found[M+H] 293.3 9. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylicacid m-tolylamide H H H H 1

¹H NMR (CD3OD) 2.34 (s, 3H), 3.11 (t, 2H), 4.24 (t, 2H), 6.89 (d, 1H),7.04 (s, 2H), 7.20 (t, 1H), 7.42 (s, 1H), 7.60 (d, 1H), 7.65 (s, 1H)LRMS calcd 292.34 found [M+H] 293.2 10. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-ethoxy- phenyl)-amide H H H H 1

¹H NMR (CD3OD) 1.37 (t, 3H), 3.10 (t, 2H), 4.01 (q, 2H), 4.23 (t, 2H),6.90 (d, 2H), 7.02 (d, 2H), 7.41 (s, 1H), 7.69 (d, 2H) LRMS calcd 322.37found [M+H] 323.3 11. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid o-tolylamide H H H H 1

¹H NMR (CD3OD) 2.37 (s, 3H), 3.12 (t, 2H), 4.24 (t, 2H), 6.91 (s, 1H),7.01 (s, 1H), 7.09 (t, 1H), 7.18 (t, 1H), 7.24 (d, 1H), 7.44 (s, 1H),7.50 (d, 1H) LRMS calcd 292.34 found [M+H] 293.3 12. 5,6-Dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (3-methoxy- phenyl)-amideH H H H 1

¹H NMR (CD3OD) 3.11 (t, 2H), 3.80 (s, 3H), 4.24 (t, 2H), 6.64 (d, 1H),7.04 (s, 2H), 7.23 (t, 1H), 7.31 (d, 1H), 7.43 (s, 1H), 7.57 (s, 1H)LRMS calcd 308.33 found [M+H] 309.2 13. {4-[(5,6- Dihydro-4H-1,3a,6-triaza-as-indacene-8- carbonyl)-amino]- benzyl}-methyl- carbamic acidtert-butyl ester H H H H 1

14. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(4-methylaminomethyl- phenyl)-amide H H H H 1

¹H NMR (CD3OD) 2.70 (s, 1H), 3.28-3.31 (m, 2H), 4.15 (s, 2H), 4.46 (t,2H), 7.35 (s, 1H), 7.45-7.49 (m, 3H), 7.81 (s, 1H), 7.87-7.90 (m, 2H)LRMS calcd 321.38 found [M+H] 322.3 15. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-fluoro- phenyl)-amide H H H H 1

16. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(3-fluoro- phenyl)-amide H H H H 1

17. 4-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylicacid [4-(2-propylamino- ethoxy)-phenyl]-amide H H H CH3 1

18. 4-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylicacid (2-fluoro-phenyl)-amide H H H CH3 1

LRMS calcd 310.33, found [M+H] 311.1 19. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid [4-(2-propylamino- ethoxy)-phenyl]-amideH H H H 1

LRMS calcd 379.46, found [M+H] 380.3 20. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3,4-difluoro- phenyl)-amide H H H H 1

¹H NMR (CD3OD) 3.16 (t, 2H), 4.30 (t, 2H), 7.10 (s, 2H), 7.21-7.29 (m,1H), 7.49-7.55 (m, 2H), 7.93-8.02 (m, 1H) LRMS calcd 314.29 found [M+H]315.1 21. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(4-trifluoromethyl- phenyl)-amide H H H H 1

¹H NMR (CD3OD) 3.12 (t, 2H), 4.25 (t, 2H), 7.06-7.07 (m, 2H), 7.46 (s,1H), 7.62 (d, 2H), 8.04 (d, 2H) LRMS calcd 346.31 found [M+H] 347.1 22.5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid{4-[2-(4-benzyl- piperidin-1-yl)-ethoxy]- 3-fluoro-phenyl}-amide H H H H1

LRMS calcd 513.61, found [M+H] 514.4 23. 5,6-Dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-2-methyl- pyridin-3-yl)-amideH H H H 1

MS found [M+H] 324.0 24. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2-methoxymethyl- pyrimidin-4-yl)-amide H H H H 1

MS found [M+H] 325.0 25. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (6-methoxy-pyridin- 3-yl)-amide H H H H 1

¹H NMR [DMSO-d6] 3.1 (t, 1H), 3.9 (s, 3H), 4.3 (t, 2H), 6.9 (d, 1H), 7.0(s, 1H), 7.2 (s, 1H), 7.5 (s, 2H), 8.2 (d, 1H), 8.6 (s, 1H), 11.8 (s,1H), 13.2 (s, 1H) 26. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (6-methoxy-pyrazin- 2-yl)-amide H H H H 1

MS found [M+H] 310.9 27. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-tert-butyl- isoxazol-3-yl)-amide H H H H 1

MS found [M+H] 326.0 28. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1-methyl-5- methylsulfanyl- 1H-[1,2,4]triazol-3-yl)-amide H H H H 1

MS found [M+H] 329.9 29. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (3-methyl- [1,2,4]thiadiazol- 5-yl)-amide H H H H 1

MS found [M+H] 300.9 30. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid thiazol-2-ylamide H H H H 1

¹H NMR [DMSO-d6] 3.1 (t, 1H), 4.3 (t, 2H), 7.0 (s, 1H), 7.2 (s, 1H), 7.3(s, 1H), 7.5 (s, 2H), 7.6 (s, 1H), 12.0 (br s, 1H), >15 (s, 1H) 31.5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(5-furan-2-yl-1H- pyrazol-3-yl)-amide H H H H 1

MS found [M+H] 334.9 32. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-methyl-pyridin- 2-yl)-amide H H H H 1

MS found [M+H] 293.9 33. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid pyridin-3-ylamide H H H H 1

MS found [M+H] 279.9 34. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid quinolin-3-ylamide H H H H 1

MS found [M+H] 329.9 35. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid pyridin-4-ylamide H H H H 1

MS found [M+H] 279.9 36. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid pyrimidin-2-ylamide H H H H 1

MS found [M+H] 280.9 37. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid pyrazin-2-ylamide H H H H 1

MS found [M+H] 280.9 38. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid pyridin-2-ylamide H H H H 1

¹H NMR [DMSO-d6] 3.1 (t, 1H), 4.3 (t, 2H), 7.0 (s, 1H), 7.1 (t, 1H), 7.2(s, 1H), 7.5 (s, 2H), 7.8 (t, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 11.8 (s,1H), 13.3 (s, 1H) 39. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-methyl- [1,3,4]thiadiazol- 2-yl)-amide H H H H 1

MS found [M+H] 300.9 40. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1H-pyrazol-3-yl)-amide H H H H 1

MS found [M+H] 269.0 41. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-methyl-isoxazol- 3-yl)-amide H H H H 1

MS found [M+H] 284.0 42. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2,5-dimethyl-2H- pyrazol-3-yl)-amide H H H H 1

MS found [M+H] 297.0 43. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1-methyl-1H- pyrazol-3-yl)-amide H H H H 1

MS found [M+H] 283.0 44. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1,3,5-trimethyl-1H- pyrazol-4-yl)-amide H H H H 1

MS found [M+H] 311.0 45. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (6-chloro-pyrazin- 2-yl)-amide H H H H 1

46. 4-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylicacid {4-[2-(4-benzyl- piperidin-1-yl)-ethoxy]- phenyl}-amide H H H CH3 1

47. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2-fluoro-phenyl)-amide H H H CH3 1

48. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2-fluoro- phenyl)-amide H H H CH3 1

49. 3-Dimethylamino- methyl-5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-fluoro- phenyl)-amide CH₂N(CH₃)₂ H H H 1

50. 4-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene-8- carboxylicacid (4-ethoxy-phenyl)-amide H H H CH3 1

51. 3-Diethylamino- methyl-5,6-dihydro-4H- 1,3a,6-triaza-as- indacene-8-carboxylic acid (2-fluoro-phenyl)-amide CH₂N(Et)₂ H H H 1

52. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (6-methoxy-pyrazin- 2-yl)-amide H H CH₃ H 1

MS found [M+H] 325.1 53. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-pyridin- 3-yl)-amide H H CH₃ H1

MS found [M+H] 323.9 54. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-2- methyl-pyridin- 3-yl)-amideH H CH₃ H 1

MS found [M+H] 338.0 55. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid p-tolylamide H H CH₃ H 1

MS found [M+H] 307.0 56. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-methoxymethyl- pyrimidin-4-yl)-amide HH CH₃ H 1

MS found [M+H] 338.9 57. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-phenyl)-amide H H CH₃ H 1

MS found [M+H] 310.9 58. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl- [1,2,4]thiadiazol-2- yl)-amideH H CH₃ H 1

MS found [M+H] 314.9 59. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2.4-difluoro-phenyl)-amide H H CH₃ H 1

MS found [M+H] 328.9 60. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-4- methoxy-phenyl)-amide H HCH₃ H 1

MS found [M+H] 341.0 61. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-methoxy-phenyl)-amide H H CH₃ H 1

MS found [M+H] 322.9 62. (R)-4-Methyl- 5,6-dihyrdro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-fluoro- phenyl)-amide H H CH₃ H 1

MS found [M+H] 310.9 63. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-2-ylamide H H CH₃ H 1

MS found [M+H] 293.9 64. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid quinolin-3-ylamide H H CH₃ H 1

MS found [M+H] 343.9 65. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-methyl-phenyl)-amide H H CH₃ H 1

MS found [M+H] 307.0 66. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyrimidin-2-ylamide H H CH₃ H 1

MS found [M+H] 294.9 67. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-4-ylamide H H CH₃ H 1

MS found [M+H] 293.9 68. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyrazin-2-ylamide H H CH₃ H 1

MS found [M+H] 294.9 69. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-pyridin- 2-yl)-amide H H CH₃ H1

MS found [M+H] 307.9 70. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-3-ylamide H H CH₃ H 1

MS found [M+H] 293.9 71. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-isoxazol- 3-yl)-amide H H CH₃ H1

MS found [M+H] 297.9 72. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-pyridin- 3-yl)-amide H H H CH₃1

MS found [M+H] 323.9 73. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-2-methyl- pyridin-3-yl)-amideH H H CH₃ 1

MS found [M+H] 337.9 74. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid p-tolylamide H H H CH₃ 1

MS found [M+H] 306.9 75. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-phenyl)-amide H H H CH₃ 1

MS found [M+H] 311.1 76. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-isoxazol- 3-yl)-amide H H H CH₃1

MS found [M+H] 297.9 77. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2- fluoro-phenyl)-amide H H CH₃ CH₃ 1

78. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (4- chloro-phenyl)-amide H H H CH₃ 1

MS found [M+H] 326.9 79. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2.4- difluoro-phenyl)-amide H H H CH₃ 1

MS found [M+H] 328.9 80. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid 4-fluoro-phenyl)-amide H H H CH₃ 1

MS found [M+H] 310.9 81. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-fluoro-phenyl)-amide H H CH₃ H 1

MS found [M+H] 293.9 82. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-4-ylamide H H H CH₃ 1

MS found [M+H] 293.9 83. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyrazin-2-ylamide H H H CH₃ 1

MS found [M+H] 294.9 84. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-3-ylamide H H H CH₃ 1

MS found [M+H] 293.9 85. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-[1,3,4]thiadiazol- 2-yl)-amideH H H CH₃ 1

MS found [M+H] 314.9 86. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-pyrazin- 2-yl)-amide H H H CH₃1

MS found [M+H] 324.9 87. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-ethoxy-phenyl)-amide H H H CH₃ 1

MS found [M+H] 337.0 88. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-4-methoxy- phenyl)-amide H H HCH₃ 1

89. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (3-methoxy-phenyl)-amide H H H CH₃ 1

90. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid quinolin-3-ylamide H H H CH₃ 1

91. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2-methyl-phenyl)-amide H H H CH₃ 1

92. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-methyl-pyridin- 2-yl)-amide H H H CH₃ 1

93. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1-methyl-1H-pyrazol- 3-yl)-amide H H H CH₃ 1

94. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1-methyl-1H-pyrazol- 3-yl)-amide H H CH₃ CH₃ 1

95. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1H-pyrazol- 3-yl)-amide H H CH₃ CH₃ 1

96. 2-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene-8- carboxylicacid (2-fluoro-phenyl)-amide CH₃ H H H 1

LRMS calcd 310.12, found [M+H] 311.1 97. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (3-methoxy-phenyl)-amide HH CH₃ CH₃ 1

MS found [M+H] 337.1 98. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-pyridin- 2-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 322.1 99. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2,4-difluoro- phenyl)-amide H H CH₃ CH₃1

MS found [M+H] 343.1 100. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-fluoro-phenyl)-amide H H CH₃ CH₃ 1

MS found [M+H] 325.1 101. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-pyridin-3-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 338.1 102. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-methoxymethyl- pyrimidin-4-yl)-amide HH CH₃ CH₃ 1

MS found [M+H] 353.1 103. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-bromo-pyridin- 3-yl)-amide H H CH₃ CH₃1

MS found [M+H] 386.0 104. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-phenyl)-amide H H CH₃ CH₃ 1

MS found [M+H] 325.1 105. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-2-methyl- pyridin-3-yl)-amideH H CH₃ CH₃ 1

MS found [M+H] 352.1 106. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-chloro-5-methyl- pyridin-3-yl)-amide HH CH₃ CH₃ 1

MS found [M+H] 356.1 107. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid [6-(3-isopropoxy- propylamino)-pyridin-3-yl]-amide H H CH₃ CH₃ 1

MS found [M+H] 423.2 108. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-pyrazin- 2-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 339.1 109. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-isoxazol- 3-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 312.1 110. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyrimidin-2-ylamide H H CH₃ CH₃ 1

MS found [M+H] 309.1 111. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyrazin-2-ylamide H H CH₃ CH₃ 1

MS found [M+H] 309.1 112. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-chloro-pyridin- 3-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 342.0 113. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid [6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-amide H H CH₃ CH₃ 1

MS found [M+H] 437.2 114. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (1-methyl-5- methylsulfanyl-1H-[1,2,4]triazol-3-yl)-amide H H CH₃ CH₃ 1

MS found [M+H] 358.1 115. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-methyl-[1,2,4]thiadiazol- 5-yl)-amideH H CH₃ CH₃ 1

MS found [M+H] 329.0 116. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methyl-pyridin- 3-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 322.1 117. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-chloro-pyridin- 2-yl)-amide H H CH₃CH₃ 1

MS found [M+H] 342.0 118. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-methyl-[1,3,4]thiadiazol- 2-yl)-amideH H CH₃ CH₃ 1

MS found [M+H] 329.0 119. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-4-methoxy- phenyl)-amide H HCH₃ CH₃ 1

MS found [M+H] 355.1 120. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-bromo-pyridin- 2-yl)-amide H H CH₃ CH₃1

MS found [M+H] 386.0 121. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-4-ylamide H H CH₃ CH₃ 1

MS found [M+H] 308.1 122. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid [6-(2-propylamino- ethoxy)-pyridin-3-yl]-amide H H CH₃ CH₃ 1

123. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid phenylamide H H CH₃ CH₃ 1

MS found [M+H] 307.1 124. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid pyridin-3-ylamide H H CH₃ CH₃ 1

125. 4-Methyl-5,6- dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylicacid [4-(2-propylamino- ethoxy)phenyl] amide H H H CH₃ 1

LRMS calcd 393.48, found [M+H] 394.4 126. 4-Methyl-5,6-dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylic acid(4-ethoxyphenyl)amide H H H CH₃ 1

LRMS calcd 336.39, found [M+H] 337.2 127. 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-fluorophenyl)amide H H H H 1

LRMS calcd 296.30, found [M+H] 297.2 128. 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-fluoro-4-methoxy- phenyl)amide H H H H1

LRMS calcd 326.33, found [M+H] 327.2 129. 4-Methyl-5,6-dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylic acid(2-fluoro-4-isopropoxy- phenyl)amide H H H CH3 1

LRMS calcd 368.40, found [M+H] 369.2 130. 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-fluoro-4-isopropoxy- phenyl)amide H HH H 1

LRMS calcd 354.38, found [M+H] 355.2 131. 4-Methyl-5,6-dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylic acid[4-(2-propylamino- ethoxy)phenyl]amide H H H CH3 1

LRMS calcd 393.48, found [M+H] 394.4 132. 4-methyl-5,6-dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylic acid{4-[2-(4-benzyl- piperidinyl)ethoxy] phenyl}amide H H H CH3 1

LRMS calcd 509.64, found [M+H] 510.5 133. 2,3-Bis- dimethylaminomethyl-5,6-dihydro-4H-1,3a,6- triaza-as-indacene- 8-carboxylic acid(2-fluoro-phenyl)-amide CH₂N(CH₃)₂ CH₂N(CH₃)₂ H H 1

134. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2-fluoro-phenyl)-amide H H CH3 CH3 1

LRMS calcd 324 found [M+1] 325 135. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-ethoxy-phenyl)-amide HH CH3 CH3 1

LRMS calcd 350 found [M+1] 351 136. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid pyridin-2-ylamide H H CH3CH3 1

LRMS calcd 307 found [M+1] 308 137. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-[1,2,4]triazol-1-ylmethyl-phenyl)-amide H H CH3 CH3 1

LRMS calcd 387 found [M+1] 388 138. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-methoxy-phenyl)-amide HH CH3 CH3 1

LRMS calcd 336 found [M+1] 337 139. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid o-tolylamide H H CH3 CH3 1

LRMS calcd 320 found [M+1] 321 140. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (3-methyl-pyridin-2-yl)-amide H H CH3 CH3 1

LRMS calcd 321 found [M+1] 322 141. 4,4-Dimethyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (2-fluoro-4-methoxy-phenyl)-amide H H CH3 CH3 1

LRMS calcd 354 found [M+1] 142. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid m-tolylamide H H CH3 H 1

MS m/z 307 143. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3,4-dimethyl- phenyl)-amide H H CH3 H 1

MS m/z 321 144. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-fluoro-4-methyl- phenyl)-amide H H CH3H 1

MS m/z 325 145. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-chloro- phenyl)-amide H H CH3 H 1

MS m/z 327 146. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3,4-difluoro- phenyl)-amide H H CH3 H 1

MS m/z 329 147. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-ethyl-phenyl)-amide H H CH3 H 1

MS m/z 321 148. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-propyl-phenyl)-amide H H CH3 H 1

149. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2,5-dimethyl- phenyl)-amide H H CH3 H 1

MS m/z 321 150. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-fluoro-5- methyl-phenyl)-amide H H CH3H 1

¹H NMR [CDCl3] 1.5 (d, 3H), 2.8 (dd, 1H), 3.1 (dd, 1H), 4.3 (q, 1H), 6.9(app s, 2H), 7.0 (app s, 2H), 7.5 (s, 1H), 8.0 (d, 1H), 11.8 (s, 1H),13.1 (s, 1H) 151. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-fluoro-4- methyl-phenyl)-amide H H CH3H 1

¹H NMR [CDCl3] 1.5 (d, 3H), 2.8 (dd, 1H), 3.1 (dd, 1H), 4.3 (q, 1H), 6.9(s, 1H), 6.95 (m, 2H), 7.0 (s, 1H), 7.5 (s, 1H), 8.0 (t, 1H), 10.8 (s,1H), 13.1 (s, 1H) 152. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-fluoro-2- methyl-phenyl)-amide H H CH3H 1

¹H NMR [CD3OD] 1.2 (d, 3H), 2.1 (s, 3H), 2.55 (dd, 1H), 2.95 (dd, 1H),4.2 (q, 1H), 6.5 (t, 1H), 6.6 (s, 1H), 6.8 (s, 1H), 6.9 (t, 1H), 7.2 (m,2H) 153. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (2,5-difluoro- phenyl)-amide H H CH3 H 1

¹H NMR [CD3OD] 1.2 (d, 3H), 2.55 (dd, 1H), 2.95 (dd, 1H), 4.2 (q, 1H),6.55 (m, 1H), 6.6 (s, 1H), , 6.8 (s, 1H), 6.85 (m, 1H), 7.2 (s, 1H), 7.8(m, 1H) 154. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (6-ethyl-pyridin- 2-yl)-amide H H CH3 H 1

¹H NMR [CD3OD] 1.0 (t, 3H), 1.2 (d, 3H), 2.45 (q, 2H), 2.5 (dd, 1H), 2.9(dd, 1H), 4.2 (q, 1H), 6.65 (d, 1H), 6.7 (s, 1H), 6.8 (s, 1H), 7.2 (s,1H), 7.4 (t, 1H), 7.8 (d, 1H) 155. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (6-chloro-pyridin-3-yl)-amide H H CH3 H 1

¹H NMR [CD3OD] 1.2 (d, 3H), 2.55 (dd, 1H), 2.95 (dd, 1H), 3.0 (s, 3H),4.2 (q, 1H), 6.6 (s, 1H), , 6.8 (s, 1H), 7.1 (d, 1H), 7.2 (s, 1H), 8.0(d, 1H), 8.6 (s, 1H) 156. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-methyl-pyridin- 2-yl)-amide H H CH3 H1

¹H NMR [CD3OD] 1.2 (d, 3H), 2.1 (s, 3H), 2.55 (dd, 1H), 2.95 (dd, 1H),4.2 (q, 1H), 6.6 (s, 1H), 6.8 (s, 1H), 6.95 (dd, 1H), 7.2 (s, 1H), 7.45(d, 1H), 8.0 (d, 1H) 157. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-propyl-pyridin- 2-yl)-amide H H CH3 H1

¹H NMR [CD3OD] 0.7 (t, 3H), 1.2 (d, 3H), 1.6 (sextet, 2H), 2.4 (t, 2H),2.5 (dd, 1H), 2.9 (dd, 1H), 4.2 (q, 1H), 6.6 (d, 1H), 6.7 (s, 1H), 6.8(s, 1H), 7.2 (s, 1H), 7.4 (t, 1H), 7.7 (d, 1H) 158. (R)-4-Methyl-5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(4-methyl-pyridin- 2-yl)-amide H H CH3 H 1

¹H NMR [CDCl3] 1.4 (d, 3H), 2.4 (s, 3H), 2.75 (dd, 1H), 3.1 (dd, 1H),4.3 (q, 1H), 6.8 (app s, 2H), 7.0 (s, 1H), 7.6 (s, 1H), 8.2 (s, 1H),8.25 (d, 1H), 10.8 (s, 1H), 13.55 (s, 1H) 159. (R)-4-Methyl-5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(6-methyl-pyridin- 2-yl)-amide H H CH3 H 1

¹H NMR [CDCl3] 1.4 (d, 3H), 2.6 (s, 3H), 2.75 (dd, 1H), 3.1 (dd, 1H),4.3 (q, 1H), 6.9 (m, 2H), 7.1 (s, 1H), 7.55 (s, 1H), 7.6 (t, 1H), 8.2(d, 1H), 10.7 (s, 1H), 13.6 (s, 1H) 160. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-ethyl-pyridin-2-yl)-amide H H CH3 H 1

¹H NMR [CDCl3] 1.3 (t, 3H), 1.4 (d, 3H), 2.7 (q, 2H), 2.75 (dd, 1H(, 3.1(dd, 1H), 4.3 (q, 1H), 6.8 (s, 1H), 6.85 (d, 1H), 7.0 (s, 1H), 7.6 (s,1H), 8.3 (m, 2H), 10.8 (s, 1H), 13.55 (s, 1H) 161. (R)-4-Methyl-5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylic acid(5-chloro-pyridin- 2-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.8 (dd, 1H), 3.2 (dd, 1H), 4.5 (q, 1H),7.0 (s, 1H), 7.3 (s, 1H), 7.6 (s, 1H), 7.9 (d, 1H), 8.4 (d, 1H), 8.5 (s,1H) 162. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-trifluoromethyl- pyridin-2-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.8 (dd, 1H), 3.2 (dd, 1H), 4.5 (q, 1H),7.0 (s, 1H), 7.3 (s, 1H), 7.6 (s, 1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.8 (s,1H) 163. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-bromo-pyridin- 2-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.8 (dd, 1H), 3.2 (dd, 1H), 4.5 (q, 1H),7.0 (s, 1H), 7.3 (s, 1H), 7.6 (s, 1H), 8.0 (d, 1H), 8.4 (d, 1H), 8.5 (s,1H) 164. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (1-methyl-1H- pyridin-3-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.8 (dd, 1H), 3.2 (dd, 1H), 3.8 (s, 3H),4.5 (1, 1H), 6.6 (s, 1H), 7.0 (s, 1H), 7.3 (s, 1H), 7.4 (s, 1H), 7.6 (s,1H), 11.8 (s, 1H), 13.1 (s, 1H), 165. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (2,5-dimethyl-2H-pyrazol-3-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.1 (s, 3H), 2.8 (dd, 1H), 3.2 (dd, 1H),3.8 (s, 3H), 4.5 (q, 1H), 6.5 (s, 1H), 7.0 (s, 1H), 7.3 (s, 1H), 7.5 (s,1H), 11.8 (s, 1H), 13.2 (s, 1H) 166. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (5-methyl-[1,3,4]thiadiazol- 2-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.5 (d, 3H), 2.7 (s, 3H), 2.9 (dd, 1H), 3.3 (dd, 1H),4.6 (q, 1H), 7.1 (s, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 12.0 (s, 1H), >14(s, 1H) 167. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-ethyl- [1,3,4]thiadiazol- 2-yl)-amide H H CH3 H 1

¹H NMR [DMSO-d6] 1.3 (t, 3H), 1.5 (d, 3H), 2.9 (dd, 1H), 3.0 (q, 2H),3.3 (dd, 1H), 4.6 (q, 1H), 7.1 (s, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 12.0(s, 1H), >14 (s, 1H) 168. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3-methyl-isoxazol- 5-yl)-amide H H CH3 H1

MS m/z 298 169. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3,4-dimethyl-isoxazol- 5-yl)-amide H HCH3 H 1

MS m/z 312 170. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2,3,4-trifluoro- phenyl)-amide H H CH3 H1

MS m/z 347 171. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (4-difluoromethoxy- phenyl)-amide H H CH3H 1

MS m/z 359 172. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-ethoxy-pyridin- 3-yl)-amide H H H CH31

LRMS 337.38 found (M+1) 338.2 173. (S)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (5-methoxy-pyridin-2-yl)-amide H H H CH3 1

LRMS calcd 323 found [M+1] 324 174. (S)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (5-ethoxy-pyridin-2-yl)-amide H H H CH3 1

LRMS calcd 337 found [M+1] 338 175. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid benzo[1,3]dioxol-5-ylamide H H CH3 H 1

MS m/z 337 176. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-chloro-pyridazin- 3-yl)-amide H H CH3H 1

MS m/z 329 177. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-cyclopropyl-2- methyl-2H-pyrazol-3-yl)-amide H H CH3 H 1

MS m/z 337 178. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-cyclopropyl- [1,3,4]thiadiazol-2-yl)-amide H H CH3 H 1

MS m/z 341 179. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-trifluoromethyl- [1,3,4]thiadiazol-2-yl)-amide H H CH3 H 1

MS m/z 369 180. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (3,4-dimethoxy- phenyl)-amide H H CH3 H 1

MS m/z 353 181. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-methyl-quinolin- 6-yl)-amide H H CH3 H1

MS m/z 358 182. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8- carboxylicacid (2-chloro-pyridin- 4-yl)-amide H H H H 1

MS m/z 314 183. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-chloro-pyridin- 4-yl)-amide H H CH3 H1

MS m/z 328 184. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-ethyl-2H-pyrazol- 3-yl)-amide H H HCH3 1

LCMS found (M+H) 312 185. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-ethyl-2H-pyrazol- 3-yl)-amide H H CH3H 1

LCMS found (M+H) 312 186. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (2-ethyl-2H-pyrazol- 3-yl)-amide H H CH3CH3 1

LCMS found (M+H) 326 187. 4,4-Dimethyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-fluoro-pyridin- 2-yl)-amide H H CH3CH3 1

LCMS found (M+H) 326 188. (R)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-fluoro-pyridin- 2-yl)-amide H H CH3 H1

LCMS found (M+H) 312 189. 5,6-Dihydro-4H- 1,3a,6-triaza- as-indacene-8-carboxylic acid (5-fluoro-pyridin- 2-yl)-amide H H H H 1

LCMS found (M+H) 297 190. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (6-methoxy-2-methyl- pyridin-3-yl)-amideH H H CH3 1

LRMS 337.38 found (M+1) 338.2 191. (S)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (5-fluoro-pyridin-2-yl)-amide H H H CH3 1

LRMS 311.11 found (M+1) 312.2 192. (S)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-propoxy-phenyl)-amide HH H CH3 1

LRMS 350.42 found (M−1) 349.2 193. (S)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (4-ethoxy-3-fluoro-phenyl)-amide H H H CH3 1

LRMS 354.38 found (M−1) 353.2 194. (R)-4-Methyl- 5,6-dihydro-4H-1,3a,6-triaza- as-indacene-8- carboxylic acid (3-propyl-[1,2,4]thiadiazol- 5-yl)-amide H H CH3 H 1

LCMS found (M+H) 343 195. (R)-3,4,5,6-Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (1-ethyl-1H-pyrazol- 3-yl)-amide H HCH3 H 1

LCMS found (M+H) 311 196. (R)-3,4,5,6-Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (1-propyl-1H-pyrazol- 3-yl)-amide H HCH3 H 1

LCMS found (M+H) 337 197. (S)-4-Methyl- 5,6-dihydro-4H- 1,3a,6-triaza-as-indacene-8- carboxylic acid (5-propoxy-pyridin- 2-yl)-amide H H H CH31

LRMS calcd [M+H] 352

Example 5a Preparation of2-Methyl-5,7-dihydro-6H-pyrrolo[2,3-h]quinoline-9-carboxylic acid ethylester

Step 1:

Di-tert-butyl dicarbonate (1.09 g, 5.02 mmol) is slowly added to thesolution of triethylamine (0.697 mL, 5.02 mmol), 4-dimethylaminopyridine(51 mg, 0.42 mmol) and 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylicacid methyl ester (0.81 g, 4.18 mmol) in dichloromethane (15 mL). Thereaction mixture is stirred at room temperature for 2 h, 8 mL sat.NaHCO₃ solution is added, the layers are separated, and the aqueousphase is extracted with dichloromethane (3×10 mL). The combined organiclayers are dried (Na₂SO₄) and evaporated. Flash chromatography on silicagel, eluting with hexanes: ethyl acetate (5:1), provides4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester (1.10 g, 89%) as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ1.605 (9H, s), 2.126 (2H, m), 2.510 (2H, t), 3.133 (2H, t),3.844 (3H, s), 7.701 (1H, s). MS (ES⁺) 294 (M+1)

Step 2:

To a solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (1.10 g, 3.74 mmol), NaI (841 mg, 5.61mmol) and triethylamine (1.56 mL, 11.22 mmol) in CH₃CN (15 mL), is addedtrimethylsilyl chloride (0.707 mL, 5.61 mmol) via syringe. The reactionmixture is stirred at room temperature for 15 h., 30 mL of ethylacetate/hexanes (1:1 with a few drops of triethylamine) is added todilute the solution. Saturated sodium bicarbonate solution (20 mL) isadded. The layers are separated and the aqueous phase is extracted withethyl acetate/hexanes (1:1) (3×10 mL). The combined organic layers aredried (Na₂SO₄) and evaporated to provide4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (1.3 g, 100%) as a viscous red oil. ¹HNMR (400 MHz, CDCl₃) δ0.180 (9H, s), 1.576 (9H, s), 2.343 (2H, m), 2.930(2H, t), 3.781 (3H, s), 4.826 (1H, t), 7.580 (1H, s). MS (ES⁺) 366 (M+1)

Step 3:

a): Alumina (3 g, neutral) is activated at 200° C. for 4 h. It is cooledto room temperature under nitrogen. ZnCl₂(1M in ether, 3.7 mL) is addedand the solution is stirred at room temperature for another 30 min,after which the solvent is removed by rotary evaporator and pump. Thefresh prepared Al₂O₃—ZnCl₂ powder is slowly added to the mixture of4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (1.3 g, 3.7 mmol) and methyl vinylketone (1.54 mL, 18.5 mmol) at 0° C. The reaction mixture is stirred at0° C. for 3 h and then diluted with 30 mL of dichloromethane. Solidresidue is filtered off. Several drops of water are added to thesolution and it is heated to a boil for one minute. The solution isdried over Na₂SO₄ and organic solvents are removed by rotary evaporator.Flash chromatography on silica gel, eluting with hexanes:ethyl acetate(6:1 to 1:1), provides a mixture (1.06 g, diketone product and startingmaterial) as intermediate.

b): A solution of the mixture (760 mg) from the last step and ammoniumacetate (804 mg, 10.45 mmol) in acetic acid (15 mL) is placed in a roundbottom flask equipped with an open-to-the-air condenser. The solution isheated at 100° C. for 4 h. Acetic acid is removed by rotary evaporator.Solid residue is dissolved in dichloromethane (20 mL) and sat. NaHCO₃(20 mL) The layers are separated and the aqueous phase is extracted withdichloromethane: 2-propanol (4:1)(4×15 mL). The combined organicsolvents are dried (Na₂SO₄) and evaporated. Flash chromatography onsilica gel, eluting with 5% MeOH/CH₃CN, provides2-methyl-5,7-dihydro-6H-pyrrolo[2,3-h]quinoline-9-carboxylic acid methylester (178 mg, 27% for two steps) as an off-white solid. ¹H NMR (400MHz, CD₃OD) δ2.453 (3H, s), 2.704 (2H, t), 2.887 (2H, s), 3.791 (3H, s),6.878 (1H, d) 7.313 (1H, s), 7.426 (1H, d). MS (ES⁺) 243 (M+1)

Example 5b Preparation of9-Methyl-3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acidethyl ester

Step 1:

Di-tert-butyl dicarbonate (4.46 g, 20 mmol) is slowly added to asolution of triethylamine (2.84 mL, 20 mmol), 4-dimethylaminopyridine(414 mg, 3.4 mmol) and4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethylester (3.8 g, 17.04 mmol) in dichloromethane (100 mL). The reactionmixture is stirred at room temperature for 45 min. Saturated sodiumbicarbonate solution (30 mL) is added, the layers are separated, and theaqueous phase is extracted with dichloromethane (4×30 mL). The combinedorganic layers are dried (Na₂SO₄) and evaporated. Flash chromatographyon silica gel, eluting with hexanes: ethyl acetate (5:1), provides4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (4.6 g 83%) as light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ1.277 (3H, t), 1.568 (9H, s), 1.855 (4H, m), 2.744(2H, m), 3.205 (2H, m), 4.229 (2H, q), 7.589 (1H, s). MS (ES⁺) 322(M+1).

Step 2:

To a solution of4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (2.17 g, 6.72 mmol), NaI (1.51 g, 10.07mmol) and triethylamine (2.80 mL, 20.14 mmol) in CH₃CN (30 mL), is addedtrimethylsilyl chloride (1.27 mL, 10.07 mmol) slowly via syringe. Thereaction mixture is stirred at room temperature for 20 h. and thenpartitioned between 50 mL of ethyl acetate/hexanes (1:1 with a few dropsof triethylamine ) and 30 mL of sat. NaHCO₃ solution. The layers areseparated and the aqueous phase is extracted with ethyl acetate/hexanes(1:1) (3×20 mL). The combined organic layers are washed with brine,dried (Na₂SO₄) and evaporated to provide4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (2.56 g, 100%) as viscous red oil.¹H NMR (400 MHz, CDCl₃) δ0.177 (9H, s), 1.308 (3H, t), 1.585 (9H, s),1.906 (2H, m), 2.016 (2H, m), 2.974 (2H, t), 4.243 (2H, q), 5.353 (1H,t), 7.627 (1H, s). MS (ES⁺) 395 (M+1).

Step 3:

a): Alumina (5 g, neutral) is activated at 200° C. for 2 h. It is cooledto room temperature under nitrogen. ZnCl₂(1M in ether, 7.1 mL) is addedand the solution is stirred at room temperature for another 30 min,after which the solvent is removed by rotary evaporator and pump. Thefreshly prepared Al₂O₃—ZnCl₂ powder is slowly added to a mixture of4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (2.56 g, 6.51 mmol) and methylvinyl ketone (5 mL, 60 mmol) at 0° C. The reaction mixture is stirred at0° C. for 2 h and diluted with 30 mL dichloromethane. Solid residue isfiltered off. Several drops of water are added to the solution and it isheated to boil for one minute. The solution is dried over Na₂SO₄ andorganic solvents are removed by rotary evaporator. Flash chromatographyon silic gel, eluting with hexanes:ethyl acetate (6:1 to 1:1), providesa mixture (1.15 g, diketone product and starting material) asintermediate.

b): A solution of the mixture (1.15 g ) from the last step and ammoniumacetate (2.3 g, 30 mmol) in acetic acid (25 mL) is placed in around-bottom flask equipped with an open-to-the-air condenser. Thesolution is heated at 100° C. for 2 h. Acetic acid is removed by rotaryevaporator. Solid residue is dissolved in dichloromethane (30 mL) andsat. NaHCO₃ (30 mL). The layers are separated and the aqueous phase isextracted with dichloromethane: 2-propanol (4:1)(3×30 mL). The combinedorganic solvents are dried (Na₂SO₄) and evaporated. Flash chromatographyon silica gel, eluting with 10% MeOH/CH₂Cl₂, provides9-methyl-3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acidethyl ester (347 mg, 18% for two steps) as an off-white solid. ¹H NMR(400 MHz, CD₃OD) δ1.192 (3H, t), 2.153 (2H, m), 2.472 (3H, s), 2.568(4H, m), 4.145 (2H, q), 7.003 (1H, d), 7.355 (1H, s), 7.521 (1H, d) MS(ES⁺) 271 (M+1)

Example 5c Preparation of3,4,5,6-Tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid ethylester

Step 1:

A solution of isoxazole (18 g, 0.26 mol) and Raney Nickel (2 g) in 200mL MeOH is hydrogenated at 50 psi for 20 h. The reaction mixture isfiltered to remove the catalyst and the solvent is evaporated to givetitle compound (12 g, 67%) as a yellow solid. mp 96-98° C. ¹H NMR (400MHz, CD₃OD) δ5.387 (1H, m), 7.395 (1H, d), 8.812 (1H, d).

Step 2:

A mixture of4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta(b)pyrrole-3-carboxylic acid ethylester (7.0 g, 31.67 mmol), 3-amino-prop-2-enal (3.37 g, 47.5 mmol) andammonium acetate (365 mg, 4.75 mmol) in triethylamine (7 mL) is heatedat 110° C. for 4 h. It is cooled to room temperature and the solidresidue is dissolved in 100 mL dichloromethane and 100 mL sat. NaHCO₃solution. Layers are separated and the aqueous phase is extracted with4:1 DCM/2-propanol (4×100 mL). Combined organic layers are dried(Na₂SO₄) and evaporated. Flash Chromatography on silica gel, elutingwith EtOAc:triethylamine (20:1), provides3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid ethylester (1.6 g, 20%) as off-white solid. ¹H NMR (400 MHz, CD₃OD) δ1.247(3H, t), 2.227 (2H, m), 2.631 (4H, m), 4.197 (2H, q), 7.170 (1H, m),7.405 (1H, s), 7.686 (1H, d), 8.375 (1H, d). MS (ES⁺) 257 (M+1)

Example 5d Preparation of3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid[1-(2-ethylaminoethyl)-2-oxo-1,2-dihydropyridin-3-yl]amide

The title compound is prepared by a slightly modified route involving arearrangement reaction to form the pyridone.

Step 1:

To a solution of 2-(tetrahydropyran-2-yloxy)ethanol (5.4 g, 36.6 mmol)and 2-chloro-3-nitropyridine (5.8 g, 36.6 mmol) in THF (50 mL) at 0° C.is added t-BuOK (1.0 M solution in t-BuOH, 44 mL). The mixture is thenstirred at room temperature overnight. The solvent is removed and theresidue is separated by column chromatography on silica gel(hexanes:ethyl acetate 4:1) to give 5.8 g of3-nitro-2-[[2-(tetrahydro-pyran-2-yloxy)-ethoxy]pyridine as an oil.

Step 2:

A mixture of 3-nitro-2-[2-(2-tetrahydro-pyran-2-yloxy)-ethoxy]pyridine(5.8 g) and 10% Pd/C (500 mg) in ethanol (30 mL) is placed in a Parrbottle and pressurized at 50-60 psi for 4 h. The resulting mixture isfiltered through Celite and concentrated in vacuo to give 5.0 g of 5.8 gof 3-amino-2-[[2-(tetrahydro-pyran-2-yloxy)-ethoxy]pyridine.

Step 3:

To a solution of 2-[2-(tetrahydropyran-2-yloxy)-ethoxy]pyridin-3-ylamine(2.3 g, 9.7 mmol) in DCM (8 mL) is added AlMe₃ (2M in toluene, 4.9 mL)at rt. After stirring at room temperature for 1 h, a solution of3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid ethylester (500 mg, 1.95 mmol) in DCM (10 mL) is added. The mixture isrefluxed overnight. On cooling, water (5 mL) is added, and the resultingmixture is extracted with DCM. The combined DCM extracts are dried andsolvent removed. The residue is separated by column chromatography onsilica gel (5% methanol in DCM) to give 850 mg of3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid{2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide as an oil.

Step 4:

A solution of 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylicacid {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide (850 mg)and p-toluenesulfonic acid monohydrate (700 mg) in methanol (30 mL) isrefluxed for 1 h. The solvent is removed and the residue is extractedwith DCM and washed with NaHCO₃ (aq.). The organic layer is dried andsolvent removed to give 700 mg of3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid[2-(2-hydroxy-ethoxy)pyridin-3-yl]amide.

Step 5:

To a mixture of3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid[2-(2-hydroxy-ethoxy)pyridin-3-yl]amide (150 mg, 0.41 mmol) andtriethylamine (125 mg, 1.2 mmol) in DCM (10 mL) at 0° C. is addedmethanesulfonyl chloride (94 mg, 0.82 mmol) dropwise. The mixture isstirred at 0° C. for 15 min. The solvent is removed and the residue isdissolved in acetonitrile (10 mL) and transferred to a sealed tube.Ethylamine (1 mL) is added and the mixture is heated at 60° C. for 3 h.The solvent is removed and the residue is separated by preparative TLCto give 87 mg of3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid[1-(2-ethylaminoethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]amide. LRMS Calcd391.5; found M−1 390.2.

Example 5e

Using the methods shown in Schemes 2 and 3 the compounds shown in Table2 were prepared.

TABLE 2

Cmp. # Name R^(3a) R³ R⁴ R⁵ R⁶ k Ar Spectral Data 1. 9-Methyl-3,4,5,6-tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid (4-methoxy-phenyl)-amide CH₃ H H H H 2

2. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (2-fluoro-phenyl)- amide CH₃ H H H H 2

3. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-fluoro-4- methoxy-phenyl)- amide CH₃ H H H H 2

4. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (4-fluoro-phenyl)- amide CH₃ H H H H 2

5. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-fluoro-phenyl)- amide CH3 H H H H 2

6. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (4-ethoxy-phenyl)- amide CH₃ H H H H 2

7. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid phenylamide CH₃ H H H H 2

8. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-methoxy- phenyl)-amide CH₃ H H H H 2

9. 9-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-ethoxy-phenyl)- amide CH₃ H H H H 2

10. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(2-fluoro-phenyl)- amide H H H H H 2

11. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(4-methoxy- phenyl)-amide H H H H H 2

12. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(3-fluoro-4- methoxy-phenyl)- amide H H H H H 2

MS found [M + H] 352.0 13. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (4-ethoxy-phenyl)- amide H H H H H 2

MS found [M + H] 348.1 14. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid pyridin-2-ylamide H H H H H 2

MS found [M + H] 305.0 15. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (1-methyl-1H- pyrazol-3-yl)- amide HH H H H 2

MS found [M + H] 308.0 16. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl- [1,3,4]thiadiazol-2-yl)-amide H H H H H 2

MS found [M + H] 326.0 17. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-fluoro-pyridin- 2-yl)-amide H H HH H 2

18. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid{4-[2-(ethyl- methanesulfonyl- amino)-ethoxy]- phenyl}-amide H H H H H 2

LRMS calcd 468 found [M + 1] 469 19. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [4-(2-ethylamino- ethoxy)-phenyl]-amide H H H H H 2

LRMS calcd 390 found [M + 1] 391 20. 8-Methyl-3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid (4-ethoxy-phenyl)- amide H CH₃H H H 2

21. 8-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid pyridin-2-ylamide H CH₃ H H H 2

22. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acidpyridin-3-ylamide H H H H H 2

MS found [M + H] 304.9 23. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (3-methyl- [1,2,4]thiadiazol-5-yl)-amide H H H H H 2

MS found [M + H] 326.0 24. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (3-propyl- [1,2,4]thiadiazol-5-yl)-amide H H H H H 2

LCMS found [M + H] 354 25. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-methyl-pyridin- 3-yl)-amide H H HH H 2

MS found [M + H] 319.1 26. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-chloro-pyridin- 2-yl)-amide H H HH H 2

MS found [M + H] 339.0 27. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-chloro-pyridin- 3-yl)-amide H H HH H 2

MS found [M + H] 339.0 28. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (2,4-difluoro- phenyl)-amide H H H HH 2

MS found [M + H] 340.1 29. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (4-chloro-phenyl)- amide H H H H H 2

MS found [M + H] 338.0 30. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid pyrimidin-2- ylamide H H H H H 2

MS found [M + H] 306.1 31. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid pyridin-4-ylamide H H H H H 2

MS found [M + H] 305.1 32. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid o- tolyl-amide H H H H H 2

MS found [M + H] 318.1 33. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-bromo-pyridin- 2-yl)-amide H H H HH 2

MS found [M + H] 383.0 34. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl-pyridin- 2-yl)-amide H H HH H 2

MS found [M + H] 319.1 35. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-methoxy- pyridin-3-yl)- amide H HH H H 2

MS found [M + H] 335.2 36. Propyl-(2-{5- [(3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carbonyl)-amino]- pyridin-2-yloxy}-ethyl)-carbamic acid tert-butyl ester H H H H H 2

MS found [M + H] 506.3 37. 8-Methyl-3,4,5,6- tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl- [1,3,4]thiadiazol-2-yl)-amide H CH₃ H H H 2

38. 8-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-fluoro-4- methoxy-phenyl)- amide H CH₃ H H H 2

39. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(4-ethoxy-phenyl)- amide H H H H H 2

MS found [M + H] 348.1 40. Ethyl-(2-{4- [(3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carbonyl)-amino]- phenoxy}-ethyl) - carbamicacid tert-butyl ester H H H H H 2

41. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(6-ethyl-pyridin- 2-yl)-amide H H H H H 2

¹H NMR [CDCl3] 1.35(t, 3H), 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H),2.8(q, 2H), 6.8(d, 1H), 7.2(dd, 1H), 7.55(t, 1H), 7.6(dd, 1H), 7.65(s,1H), 8.2(d, 1H), 8.75(d, 1H), 9.2(br s, 1H) 42. 3,4,5,6-Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acidbenzo[1,3]dioxol- 5-ylamide H H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H), 6.8(d, 1H),7.1(d, 1H), 7.2(dd, 1H), 7.5(s, 1H), 7.6(s, 1H), 7.65(d, 1H), 8.6(d,1H), 9.7(br s, 1H) 43. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (2-chloro-pyridin- 4-yl)-amide H H HH H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H), 7.2(dd, 1H),7.5(d, 1H), 7.6(s, 1H), 7.65(d, 1H), 7.8(s, 1H), 8.2(d, 1H), 8.6(d, 1H),9.0(br s, 1H) 44. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-methoxy- phenyl)-amide H H H H H 2

[CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H), 3.8(s, 3H), 6.6(app s,1H), 7.2(dd, 1H), 7.25(app s, 2H), 7.6(m, 2H), 8.6(d, 1H), 9.9(br s, 1H)45. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(2,5-difluoro- phenyl)-amide H H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H), 6.7(m, 1H),7.0(m, 1H), 7.2(dd, 1H), 7.6(dd, 1H), 7.65(s, 1H), 8.5(m, 1H), 8.6(d,1H), 9.2(br s, 1H) 46. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-methyl-pyridin- 2-yl)-amide H H HH H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.4(s, 3H), 2.6(t, 2H), 2.7(t, 2H),6.8(d, 1H), 7.2(dd, 1H), 7.5(t, 1H), 7.6(dd, 1H), 7.65(s, 1H), 8.2(d,1H), 8.7(d, 1H), 9.8(br s, 1H) 47. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (3-methyl- isoxazol-5-yl)- amide H HH H H 2

¹H NMR [CDCl3] 2.25(s, 3H), 2.3(quint, 2H), 2.6(t, 2H), 2.7(t, 2H),6.3(s, 1H), 7.2(dd, 1H), 7.6(m, 2H), 8.6(d, 1H), 8.8(br s, 1H) 48.3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(2,3-dihydro- benzo[1,4]dioxin- 6-yl)-amide H H H H H 2

LRMS m/z 362 49. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-isopropoxy- phenyl)-amide H H H H H 2

LRMS m/z 362 50. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3,4-dihydro-2H- benzo[b][1,4]dioxepin- 7-yl)-amide H HH H H 2

LRMS m/z 376 51. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid(4- trifluoromethoxy- phenyl)-amide H H H H H 2

LRMS m/z 388 52. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (4-phenoxy- phenyl)-amide H H H H H 2

LRMS m/z 396 53. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid pyrazin-2-ylamide H H H H H 2

LRMS m/z 306 54. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (1-ethyl-1H- pyrazol-3-yl)- amide H H H H H 2

LCMS found (M + H) 322 55. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl-1H- pyrazol-3-yl)- amide HH H H H 2

LCMS found (M + H) 309 56. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6-yl)- amide H H H H H 2

LCMS found (M + H) 363 57. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl- [1,3,4]thiadiazol-2-yl)-amide H H H H H 2

58. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acidpyridin-3-ylamide H H H H H 2

59. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid[6-(3-isopropoxy- propylamino)- pyridin-3-yl]- amide H H H H H 2

MS found [M + H] 420.3 60. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-methoxy- pyrazin-2-yl)- amide H HH H H 2

MS found [M + H] 336.2 61. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-methyl- isoxazol-3-yl)- amide H HH H H 2

MS found [M + H] 309.2 62. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (1H-pyrazol-3-yl)- amide H H H H H 2

MS found [M + H] 294.2 63. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (3-fluoro-phenyl)- amide H H H H H 2

MS found [M + H] 322.2 64. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [6-(2-morpholin-4- yl-ethoxy)-pyridin-3-yl]- amide H H H H H 2

MS found [M + H] 434.4 65. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (5-bromo-pyridin- 3-yl)-amide H H H HH 2

MS found [M + H] 383.1 66. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-bromo-pyridin- 3-yl)-amide H H H HH 2

MS found [M + H] 383.2 67. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [4-(2-ethoxy- ethoxy)-phenyl]- amideH H H H H 2

¹H NMR(DMSO) 1.11(t, 3H), 2.15(t, 2H), 2.49(t, 2H), 2.73(t, 2H),3.46-3.49(m, 2H), 3.67(t, 2H), 4.0(t, 2H), 6.90- 6.92(m, 2H),7.58-8.41(m, 5H), 8.69(brs, 1H) LCMS found (M + H) 392.3 68. 3,4,5,6-Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(3-ethoxy-phenyl)- amide H H H H H 2

LCMS found (M + H) 348 69. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid (6-ethoxy-pyridin- 2-yl)-amide H H HH H 2

LCMS found (M + H) 349 70. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [4-(1-ethyl- azetidin-3-yloxy)-phenyl]-amide H H H H H 2

Electrospray mass spectrum: m/z 401.4 [M − 1] 71. 3,4,5,6-tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylic acid(5-ethoxy-pyridin- 2-yl)-amide H H H H H 2

LRMS calcd 348 found [M + 1] 349 72. 8-Methyl-3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid (5-methoxy- pyridin-2-yl)-amide H CH₃ H H H 2

LRMS calcd 348 found [M + 1] 349 73. 8-Methyl-3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid (5-ethoxy-pyridin- 2-yl)-amideH CH₃ H H H 2

LRMS calcd 362 found [M + 1] 363 74. 8-Methyl-3,4,5,6- tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid pyridazin-3- ylamide H CH₃ H HH 2

¹H NMR (CD3OD): 2.25(t, 2H), 2.35(s, 3H), 2.55-2.7(tt, 4H), 7.55-7.65(m, 3H), 8.58.6(m, 2H), 8.85(d, 1H); LRMS calcd 319 found [M + 1]320 75. 8-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (3-methyl- isoxazol-5-yl)- amide H CH₃ H H H 2

¹H NMR (CD3OD): 2.2-2.3(m, 5H), 2.40(s, 3H), 2.6- 2.7(tt, 4H), 6.2(s,1H), 7.55-7.6(ss, 2H), 8.45(s, 1H); LRMS calcd 322 found [M + 1] 323 76.8-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylicacid (5-methyl- isoxazol-3-yl)- amide H CH₃ H H H 2

¹H NMR (CD3OD): 2.25(t, 2H), 2.35-2.40(ss, 6H), 2.55- 2.7(tt, 4H),6.7(s, 1H), 7.55-7.65(ss, 2H), 8.4(s, 1H); LRMS calcd 322 found [M + 1]323 77. 3,4,5,6- Tetrahydro-3,10- diaza- benzo[e]azulene-1- carboxylicacid (6-ethylamino- pyridin-3-yl)- amide H H H H H 2

LRMS calcd 347 found [M + 1] 323 78. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid(1- methyl-1H-pyrazol- 3-yl)-amide HCH₃ H H H 2

LRMS 320 (M − 1) 79. 3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1-carboxylic acid(5- ethyl- 1,3,4]thiadiazol-2- yl)amide H H H H H 2

LRMS calcd 339.4 found [M − 1] 338.2 80. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid(5- trifluoromethyl-[1,3,4]thiadiazol- 2-yl)amide H H H H H 2

LRMS calcd 379.4 found [M − 1] 378.2 81. 3,4,5,6- Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid [1,3,4]thiadiazol- 2-ylamide HH H H H 2

LCMS found (M − H) 310 82. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-dimethylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 404.4 [M − 1] 83. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-dimethylamino- ethoxy)-pyridin-2-yl]-amide H H H H H 2

LRMS: m/z 390.3 [M − 1] 84. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-pyrrolidin-1-yl-ethoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 416.3 [M − 1] 85. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (3-cyclobutylamino-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 1.65(m, 4H), 1.9-2.2(m, 6H), 2.4-2.7(m, 6H), 3.2(m, 1H),4.05(t, 2H), 6.75(d, 1H), 7.05(m, 1H), 7.3(d, 1H), 7.6(m, 2H), 8.6(d,1H), 10.5(br, 1H), 13.7(br, 1H) LRMS calcd 404 found [M + 1] 405 86.Methyl-(2-{3- [(3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carbonyl)-amino]- pyridin-2-yloxy}- ethyl)-carbamic acid tert-butylester H H H H H 2

¹H NMR(CDCl3) 1.39(s, 9H); 2.25(m, 2H); 2.62(m, 4H); 2.84(s, 3H);3.62(t, 2H); 4.61(t, 2H); 6.88(m, 1H); 7.15(m, 1H); 7.60(m, 2H),;7.80(m, 1H); 8.58(m, 1H); 8.68(d, 1H); 9.59(br s, 1H); 12.62(br s, 1H);LRMS calcd 477 # found [M + 1] 478 87. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[2- (2-methylamino- ethoxy)-pyridin-3-yl]-amide H H H H H 2

¹H NMR(CDCl3) 2.22(m, 2H); 2.39(s, 3H); 2.60(m, 4H); 3.00(t, 2H);4.61(t, 2H); 6.88 dd, 1H); 7.10(dd 1H); 7.60(m, 2H); 7.820(dd, 1H);8.52(m, 2H); 10.1(br s, 1H) 88. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid [1- (3-hydroxy-propyl)-1H-pyrazol-3-yl]- amide H H H H H 2

¹H NMR [CDCl3] 2.0-2.3(m, 4H), 2.5-2.8(m, 4H), 3.7(m, 2H), 4.2(t, 2H),6.75(d, 1H), 7.15(m, 1H), 7.3(d, 1H), 7.6(m, 2H), 8.6(d, 1H), 9.8(br,1H); LRMS 350 (M + 1) 89. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid [1- (3-ethylamino-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 1.05(t, 3H), 2.0-2.4(m, 4H), 2.5-2.7(m, 8H), 4.15(t, 2H),6.75(d, 1H), 7.05(m, 1H), 7.3(d, 1H), 7.6(m, 2H), 8.6(d, 1H), 10.05(br,1H); LRMS 377(M − 1) 90. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid [1- (3-imidazol-1-yl-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 2.2-2.7(m, 8H), 4.05(t, 4H), 6.8(d, 1H), 7.0-7.2(m, 3H),7.25(d, 1H), 7.6(m, 3H), 8.6(d, 1H), 9.7(br, 1H); LR-MS 402 (M + 1) 91.3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1- carboxylic acid[1-(3-propylamino- propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 0.9(t, 3H), 1.50(t, 2H), 1.90-2.30(m, 6H), 2.40- 2.70(m,6H), 4.05(t, 2H), 6.70(d, 1H), 7.10(m, 1H), 7.55(m, 2H), 8.60(d, 2H),9.80(bs, 1H), 13.6(bs, 1H). 92. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid{1- [3-(cyclopropylmethyl-amino)-propyl]-1H- pyrazol-3-yl}-amide H H H H H 2

¹H NMR [CDCl3] 0.5(d, 2H), 1.45(d, 2H), 0.95(m, 1H), 2.0-2.8(m, 12H),4.05(t, 2H), 6.7(d, 1H), 7.1(m, 1H), 7.3(d, 1H), 7.6(m, 2H), 8.6(d, 1H),9.4(br, 1H); LR-MS 405 (M + 1) 93. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid(3- methyl-isothiazol- 5-yl}-amide H HH H H 2

¹H NMR(CDCl3): 2.30(t, 2H), 2.40(s, 3H), 2.60(t, 2H), 2.80(t, 2H),6.62(s, 1H), 7.20(m, 1H), 7.60-7.70(m, 2H), 8.55(dd, 1H), 10.7(bs, 1H).94. 3,4,5,6-Tetrahydro- 10-aza- benzo[e]azulene-1- carboxylic acid[6-(3-ethyllamino- propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 404.4 [M − 1] 95. 3,4,5,6-Tetrahydro- 10-aza-benzo[e]azulene-1- carboxylic acid[6- (3-propylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 418.3 [M − 1] 96. 3,4,5,6-Tetrahydro- 10-aza-benzo[e]azulene-1- carboxylic acid[6- (3-cyclobutylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 430.4 [M − 1] 97. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (3-hydroxy- propoxy)-pyridin-2-yl]-amide H H H H H 2

LRMS: m/z 377.3 [M − 1] 98. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-hydroxy-ethyl)-1H-pyrazol-3-yl]- amide H H H H H 2

¹H NMR(CDCl3): 2.20(t, 2H), 2.5-2.80(m, 6H), 6.80(s, 1H), 7.15(m, 1H),7.30(s, 1H), 7.6(m, 2H), 8.55(m, 1H), 9.70(bs, 1H), 13.7(bs, 1H) 99.3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1- carboxylic acid[1-(3-isopropylamino- propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

LRMS calcd 392 found [M − 1] 391 100. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (3-isobutylamino-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 0.9(d, 6H), 1.75(M. 1H), 2.0-2.4(M, 6H), 2.4-2.7(m, 6H),4.05(t, 2H), 6.75(d, 1H), 7.05(m, 1H), 7.25(d, 1H), 7.55- 7.6(m, 2H),8.6(d, 1H), 10.2(br, 1H); LRMS calcd 406 found [M + 1] 407 101.3,4,5,6-Tetrahydro- 3,8,10-triaza- benzo[e]azulene-1- carboxylicacid[1-(3- cyclopentylamino- propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

LRMS calcd 418 found [M + 1] 419 102. 3,4,5,6-Tetrahydro- 3,8,10-triaza-benzo[e]azulene-1- carboxylic acid [1- (3-pyrrolidin-1-yl-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

LRMS calcd 404 found [M + 1] 405 103. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-hydroxy-ethoxy)-pyridin-2-yl]-amide H H H H H 2

LRMS: m/z 363.2 [M − 1] 104. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-ethylamino- ethoxy)-pyridin-2-yl]-amide H H H H H 2

LRMS: m/z 390.2 [M − 1] 105. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-cyclobutylamino-ethyl)-6-oxo-1,6- dihydro-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 416.3 [M − 1] 106. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-ethylamino- ethyl)-1H-pyrazol-3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 1.10(t, 3H), 2.30(t, 2H), 2.50-2.80(m, 6H), 3.05(t, 2H),4.05(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.3(m, 2H), 8.60(d, 2H), 9.15(bs,1H), 13.7(bs, 1H). 107. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-propylamino- ethyl)-1H-pyrazol-3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 0.9(t, 3H), 1.50(t, 2H), 2.20(t, 2H), 2.50-2.80(m, 6H),3.05(t, 2H), 4.05(t, 2H), 6.80(d, 1H), 7.10(m, 1H), 7.30(d, 1H), 7.60(m,2H), 8.60(d, 1H), 9.90(bs, 1H), 13.7(bs, 1H). 108. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[1- (2-tert-butylamino-ethyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 1.05(s, 9H), 2.25(t, 2H), 2.50-2.70(m, 6H), 3.05(t, 2H),4.10(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.30(d, 1H), 7.60(m, 2H), 8.60(d,1H), 9.50(bs, 1H), 13.7(bs, 1H). 109. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-pyrrolidin-1-yl-ethyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 1.75(m, 4H), 2.25(t, 2H), 2.50-2.70(m, 6H), 2.95(t, 2H),4.20(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.30(d, 1H), 7.60(m, 2H), 8.60(d,1H), 9.90(bs, 1H), 13.65(bs, 1H). 110. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[2- (2-hydroxy-ethoxy)-pyridin-3-yl]-amide H H H H H 2

LRMS calcd 364.4 found [M − 1] 363.0 111. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[1- (2-ethylamino-ethyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H H H H 2

LRMS calcd 391.5 found [M − 1] 390.2 112. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[1- (3-tert-butylamino-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 1.05(s, 9H), 2.25(t, 2H), 2.50-2.70(m, 6H), 3.05(t, 2H,4.10(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.30(d, 1H, 7.60(m, 2H, 8.60(d,1H), 9.50(bs, 1H), 13.7(bs, 1H). 113. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-tert-butylamino-ethyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H H H H 2

¹H NMR(CDCl3) 1.39(s, 9H); 2.22(m, 2H); 2.59(t, 2H; 2.67(t, 2H); 3.42(t,2H); 4.50(t, 2H); 6.11(t, 1H); 7.12(m, 2H); 7.58(dd, 1H); 7.70(d, 1H);8.36(d, 1H); 8.80(dd, 1H); 9.42(br s, 1H 114. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[2- oxo-1-(2-propylamino-ethyl)- 1,2-dihydro- pyridin-3-yl]-amide H H H H H 2

¹H NMR(CDCl3) 0.91(t, 3H); 1.58(m, 2H; 2.22(m, 2H; 2.60(m, 6H; 3.10(t,2H); 4.20(t, 2H); 6.18(t, 1H); 7.00(dd, 1H); 7.10(dd, 1H); 7.58(m, 2H);8.59(d, 1H); 8.82(d, 1H); 9.20(br s, 1H); 13.28(br s, 1H); LRMS calcd405.5 found [M − 1] 404.3 115. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (3-butylamino- propoxy)-pyridin-2-yl]-amide H H H H H 2

¹H NMR [CDCl3] 0.85(t, 3H), 1.3(t, 2H), 1.47(t, 2H), 1.9(t, 2H), 2.2(t,2H), 2.49-2.57(m, 2H), 2.6(t, 2H), 2.8(t, 2H), 3.0- 3.5(m, 2H), 4.36(s,2H), 6.4(d, 1H), 7.26(t, 1H), 7.5(s, 1H), 7.6(t, 1H), 7.8(d, 1H), 8.6(d,1H); LRMS: m/z 432.5 [M − 1] 116. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (3-isobutylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 432.4 [M − 1] 117. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (3-tert-butylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 432.4 [M − 1] 118. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (3- cyclopentylamino-propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 444.3 [M − 1] 119. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[6- (2-propylamino- ethoxy)-pyridin-2-yl]-amide H H H H H 2

LRMS: m/z 405.0 [M − 1] 120. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-azetidin-1-yl-ethyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR(CDCl3): 2.0(t, 2H), 2.25(m, 2H), 2.6(tt, 4H), 2.9(t, 2H), 3.2(t,4H), 4.05(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.3(m, 2H), 8.60(d, 2H),9.6(bs, 1H), 13.6(bs, 1H). 121. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (2-diethylamino-ethyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹NMR(CDCl3): 1.0(t, 6H), 2.20(t, 2H), 2.50-2.80(m, 6H), 2.9(t, 2H),4.1(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.3(m, 2H, 8.60(d, 2H), 9.6(bs,1H), 13.6(bs, 1H). 122. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid(2- oxo-1,2-dihydro-pyridin-3-yl)-amide H H H H H 2

¹H NMR (CDCl3) 2.13(m, 2H); 2.46(m, 4H); 6.18(t, 1H); 6.84(dd, 1H);6.98(dd, 1H); 7.40(s, 1H); 7.48(dd, 1H0; 8.49(dd, 1H); 8.60(dd, 1H) 123.3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1- carboxylic acid[1-(2-cyclobutylamino- ethyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H HH H 2

LRMS calcd 417.5 found [M − 1] 416.3 124. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[2- (3-benzyloxy-propoxy)-pyridin-3- yl]-amide H H H H H 2

¹H NMR(CDCl3) 2.12(m, 2H); 2.22(m, 2H); 2.63(m, 4H); 3.58(t, 2H);4.24(s, 2H); 4.62(t, 2H); 6.84(dd, 1H); 7.05(dd, 1H); 7.31(m, 5H);7.59(dd, 1H); 7.62(d, 1H); 7.83(dd, 1H); 8.58(dd, 1H); 8.63(dd, 1H);9.84(br s, 1H); LRMS calcd 468.6 found [M − 1] 467.4 125.3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1- carboxylic acid[2-(3-hydroxy- propoxy)-pyridin-3- yl]-amide H H H H H 2

¹H NMR(DMSO- d6) 1.85(m, 2H); 2.19(m, 2H); 2.57(m, 4H); 3.45(m, 2H);4.48(m, 2H); 6.91(m, 1H); 7.22(m, 1H); 7.43(s, 1H); 7.78(m, 2H); 8.51(m,2H); 11.60(br s, 1H); 12.42(br s, 1H) 126. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[1- (3-diethylamino-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR (CDCl3): 1.05(t, 6H), 2.05(t, 2H), 2.25(t, 2H), 2.40-2.80(m, 8H),4.10(t, 2H), 6.75(d, 1H), 7.10(m, 1H), 7.30(d, 1H), 7.60(m, 2H), 8.60(d,1H), 9.30(bs, 1H), 13.55(bs, 1H). 127. 3,4,5,6-Tetrahydro-3,8,10-triaza- benzo[e]azulene-1- carboxylic acid[1- (3-piperidin-1-yl-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 1.45(m, 2H), 1.6(m, 4H), 2.0-2.7(m, 14H, 4.05(t, 2H),6.75(d, 1H), 7.05(m, 1H), 7.3(d, 1H), 7.6(m, 2H), 8.6(d, 1H), 10.2(br,1H); LRMS 417(M − 1) 128. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (3-diethylamino-propyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H H H H 2

LRMS calcd 433.6 found [M + 1] 434.1 129. 3,4,5,6-Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid[1- (3-ethylamino-propyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H H H H 2

¹H NMR(CDCl3) 1.13(t, 3H); 2.00, m, 2H); 2.24(m, 2H); 2.62(M, 6H);4.13(t, 2H); 6.20(t, 1H); 6.97(dd, 1H); 7.12(m, 1H); 7.58(d, 1H);7.60(s, 1H); 8.62(d, 1H); 8.90(d, 1H); 13.26(br s, 1H) 130.3,4,5,6-Tetrahydro- 3,10-diaza- benzo[e]azulene-1- carboxylic acid[1-(2-diethylamino- ethyl)-2-oxo-1,2- dihydro-pyridin-3- yl]-amide H H H HH 2

¹H NMR(CDCl3) 1.00(t, 6H); 2.18(m, 2H); 2.57(m, 8H); 2.79(m, 2H);4.02(m, 2H); 6.17(t, 1H); 6.97(d, 1H0; 7.08(m, 1H); 7.57(m, 2H); 8.62(d,1H); 8.87(d, 1H0; 9.73(br s, 1H0; 13.30(br s, 1H; 131.3,4,5,6-Tetrahydro- 10-aza- benzo[e]azulene-1- carboxylic acid[6-(3-diethylamino- propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS: m/z 432.4 [M − 1] 132. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid phenylamide H H H H H 2

¹H NMR(CDCl3): 2.3(t, 2H), 2.6(m, 4H), 7.10(m, 1H), 7.0-7.2(m, 2H),7.30(t, 2H), 7.60- 7.8(m, 4H), 8.60(d, 1H), 8.8(bs, 1H), 13.9(bs, 1H);LCMS found (M + H) 304 133. 3,4,5,6-Tetrahydro- 3,10-diaza-benzo[e]azulene-1- carboxylic acid[1- (3-azetidin-1-yl-propyl)-1H-pyrazol- 3-yl]-amide H H H H H 2

¹H NMR [CDCl3] 1.8-2.7(m, 14H), 3.05(m, 2H), 4.05(t, 2H), 6.75(d, 1H),7.1- 7.8(m, 4H), 8.6(M, 1H), 9.8(br, 1H); LRMS found [M + 1] 391 134.3,4,5,6-Tetrahydro- 10-aza- benzo[e]azulene-1- carboxylic acid[6-(3-pyrrolidin-1-yl- propoxy)-pyridin-2- yl]-amide H H H H H 2

LRMS calcd 431.5 found [M − 1] 430.4 135. 3,4,5,6- Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid [1-(2-morpholin-4-yl-ethyl)-2-oxo- 1,2-dihydro- pyridin-3-yl]- amide H H H H H 2

LRMS calcd 433.5 found [M + 1] 434.5 136. 3,4,5,6- Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid [1-(2-azetidin-1-yl-ethyl)-2-oxo- 1,2-dihydro- pyridin-3-yl]- amide H H H H H 2

LRMS calcd 403.4 found [M + 1] 404.4 137. 3,4,5,6- Tetrahydro-3,10-diaza- benzo[e]azulene-1- carboxylic acid (1-piperidin-4-yl-1H-pyrazol-3- yl)-amide H H H H H 2

MS m/z [M − 1] 375 138. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid {1-[3-(2-methoxy-ethylamino)-propyl]- 1H-pyrazol-3- yl}-amide H H H H H 2

¹H NMR [CDCl3] 2.0- 2.2(m, 4H), 2.5-2.8(m, 8H), 3.35(t, 2H), 3.5(t, 2H),4.05(t, 2H), 6.75(d, 1H), 7.1(m, 1H), 7.25(d, 1H), 7.6(m, 2H), 8.6(d,1H), 10.0(br, 1H) 139. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [1-(3-morpholin-4- yl-propyl)-1H-pyrazol-3-yl]- amide H H H H H 2

¹H NMR [CDCl3] 2.0- 2.3(m, 6H), 2.4(m, 4H), 2.5-2.7(m, 4H), 3.7(m, 4H),4.05(t, 2H), 6.75(d, 1H), 7.1(m, 1H), 7.25(d, 1H), 7.6(m, 2H), 8.6(d,1H), 10.5(br, 1H) 140. 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene-1- carboxylic acid [5-(3- diethylamino-propoxy)-pyridin- 2-yl]-amide H H H H H 2

141. 8-Methyl-3,4,5,6- tetrahydro-3,10- diaza- benzo[e]azulene-1-carboxylic acid (1-methyl-1H- pyrazol-3- yl)-amide H CH₃ H H H 2

Example 63-Methyl-3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acidethyl ester

Step 1:

To a solution of4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethylester (4.80 g, 21.7 mmol) and Et₃N (3.93 mL, 28.2 mmol) in CH₂Cl₂(40 mL)at 0° C. is added Boc₂O (5.68 g, 26.0 mmol) in one portion. The reactionmixture is allowed to stir at 0° C. for 10 min. and then at roomtemperature for 18 h. The reaction mixture is then diluted with halfsaturated aq NH₄Cl (70 mL) and extracted with EtOAc. The organic layeris then washed with H₂O (50 mL) and brine (50 mL). The aqueous washesare reextracted once with EtOAc, and the combined extracts are driedover Na₂SO₄ and concentrated. The crude material is purified by flashchromatography on silica gel. Elution with 4:1 hexanes-ethyl acetatefollowed by 3:1 hexanes-ethyl acetate afforded 7.00 g (quant) of4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester as a light yellow solid. ¹H NMR (CDCl₃,300 MHz) δ7.62 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.22 (m, 2H), 2.78 (m,2H), 1.86 (m, 4H), 1.60 (s, 9H), 1.31 (t, J=7.2 Hz)

Step 2:

A mixture of4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (1.13 g, 3.52 mmol) andtris(dimethylamino)methane (1.02 g, 7.04 mmol) is stirred at 60° C. in asealed tube for 4.5 h. After cooling, the thick slurry is taken up inEt₂O and filtered. The solid is washed with Et₂O and dried, affording847 mg (87%) of5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylicacid ethyl ester as a light yellow-orange solid. ¹H NMR (CDCl₃, 300 MHz)δ9.93 (br s, 1H), 7.58 (s, 1H), 7.12 (d, J=2.7 Hz, 1H), 4.21 (q, J=7.2Hz, 2H), 3.06 (s, 6H), 2.68 (m, 2H), 2.47 (m, 2H), 1.80 (m, 2H), 1.26(t, J=7.2 Hz, 3H).

Step 3:

A mixture of5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester (840 mg) and formamidineacetate (956 mg, 9.1 mmol) in EtOH (10 mL) is stirred at 120° C. for 4h. After cooling, the reaction mixture is diluted with CH₂Cl₂ and washedwith half saturated aq NaHCO₃ (25 mL), H₂O (25 mL), and brine (25 mL)The aqueous washes are reextracted once with CH₂Cl₂, and the combinedextracts are dried over K₂CO₃ and concentrated. The crude material ispurified by flash chromatography on silica gel. Elution with 30:1CHCl₃-MeOH followed by 20:1 CHCl₃-MeOH and finally 15:1 CHCl₃-MeOHafforded 606 mg (77%) of3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethylester as a light yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ9.30 (br s, 1H),9.02 (s, 1H), 8.43 (s, 1H), 7.24 (d, J=2.7 Hz, 1H), 4.26 (q, J=7.2 Hz,2H), 2.78 (t, J=7.2 Hz, 2H) 2.70 (m, 2H), 2.12 (m, 2H), 1.26 (t, J=7.2Hz, 3H).

Example 7 3,4,5,6-Tetrahydro-3,8,10-triaza-benzo[e]azulene -1-carboxylicacid 2-fluoro-phenyl-amide

To a solution of 2-fluoroaniline (108 mg, 0.972 mmol, in CH₂Cl₂ (2.0 mL)at 0° C. under N is slowly added AlMe ₃ (0.49 mL, 2.0 M in toulene). Theresulting solution is stirred at room temperature for 1 h. Next3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethylester (50 mg, 0.194 mmol) is added in one portion. The resulting mixtureis then stirred at reflux for 2 h. After cooling the reaction mixture iscarefully diluted with saturated aq NH₄Cl (˜5 mL and some H₂O. Themixture is stirred vigorously for 15 min. and then extracted three timeswith CH₂Cl₂. The combined extracts are dried over K₂CO₃ andconcentrated. The crude material is purified by flash chromatography onsilica gel. Elution with 40:1 CHCl₃—MeOH followed by 30:1 CHCl₃-MeOH andfinally 20:1 CHCl₃—MeOH afforded 45 mg (72%) of3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid2-fluoro-phenyl-amide as a light yellow solid. Electrospray massspectrum: m/z 321 [M−1].

Example 7a3-Methyl-4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxcylicacid ethyl ester

Step 1:

To a mixture of4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (4.6 mmol), sodium iodide (9.3 mmol),and triethylamine (13.9 mmol) in 15 mL acetonitrile is addedtrimethylsilyl chloride (9.3 mmol). After stirring at RT for 2 hours itis quenched with 20 mL saturated NaHCO₃ solution and extracted severaltimes with EtOAc. The combined organic layers are dried over Na₂SO₄ andevaporated in vacuo yielding4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester as a brown oil (95%). ¹H NMR(CDCl₃) 0.15 (s, 9H), 1.32 (t, 3H), 1.60 (s, 9H), 1.83-1.97 (m, 2H),1.99-2.06 (m, 2H), 3.00 (t, 2H), 4.33 (q, 2H), 5.40 (t, 1H), 7.62 (s,1H)

Step 2:

Bismuth (III) chloride (0.1 mmol) and sodium iodide (0.3 mmol) aretransferred to a dried flask under nitrogen and 5 mL of a mixture ofCH₂Cl₂/ether (9/1) is added by a syringe. This is followed by theaddition of acetyl chloride (2.2 mmol) and the suspension is stirred for5 min at RT.4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (2 mmol) in 5 mL of the samesolvent mixture is added. After 2 hours at RT, the mixture is quenchedwith 20 mL saturated NaHCO₃ solution and extracted several times withCH₂Cl₂. The organic layers are combined, dried over Na₂SO₄ andevaporated in vacuo yielding5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester as an oil (86%). LRMS 363.4 found(M+1) 364.2

Step 3:

In a sealed tube are5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and formamidine acetate(5.5 mmol) and 10 mL EtOH. The mixture is heated at 120° C. for 48hours. The solvent is evaporated in vacuo and the residue is taken up inCH₂Cl₂ and washed two times with NaHCO₃ (aq). The organic layer is driedover Na₂SO₄ and evaporated in vacuo and the residue chromatographedusing 10% MeOH in CH₂Cl₂ as mobile phase to yield7-Methyl-3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylicacid ethyl ester (36%). LRMS 271.1 found (M+1) 272

Example 7b

Using the methods shown in Scheme 4 and further illustrated in Examples6 and 7-7a the following compounds shown in Table 3 were synthesized.

TABLE 3

Cmp # Name R³ R⁴ R⁵ R⁶ k Ar Spectral Data 1 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (5-ethoxy-pyridin-2-yl)- amide H H H H 2

Electrospray mass spectrum: m/z 348 [M − 1] 2 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (5-n-propoxy-pyridin-2-yl)- amide H H H H 2

LRMS calcd 363 found [M + 1] 364 3 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (4-ethoxy- phenyl)-amide H H H H 2

Electrospray mass spectrum: m/z 347 [M − 1] 4 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (4-fluoro-phenyl)-amide H H H H 2

5 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid[4-(2- propylamino- ethoxy)-phenyl]- amide H H H H 2

LRMS calcd 405 found [M + 1] 406 6 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-methyl-oxazol- 2-yl)-amide H H H H2

LCMS found (M + H) 336 7 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-ethoxy- phenyl)-amide H H H H 2

LCMS found (M + H) 349 8 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-propyl- [1,2,4]thiadiazol-5-yl)-amide H H H H 2

LCMS found (M + H) 355 9 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-ethoxy- pyridin-3-yl)- amide H H HH 2

LRMS 349.39 found (M + 1) 350.3 10 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-methyl- [1,3,4]thiadiazol-2-yl)-amide H H H H 2

Electrospray mass spectrum: m/z 325 [M − 1] 11 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (6-ethylamino-pyridin-3-yl)- amide H H H H 2

LRMS calcd 348 found [M + 1] 349 12 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-fluoro- phenyl)-amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 6.8(app s, 1H),7.3(m, 2H), 7.7(s, 1H), 7.8(d, 1H), 8.6(s, 1H), 9.2(s, 1H), 10.4(br s,1H), 13.0(s, 1H); LRMS calcd 322 found [M + 1] 323 13 3,4,5,6-Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid(3-methoxy- phenyl)-amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 3.8(s, 3H),6.6(d, 1H), 7.2(m, 2H), 7.6(s, 1H), 7.7(s, 1H), 8.6(s, 1H), 9.2(s, 1H),10.4(br s, 1H), 12.9(s, 1H) 14 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid o-tolyl-amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.4(s, 3H), 2.6(app (t, 4H), 7.1(t, 1H),7.2(m, 2H), 7.65(s, 1H), 7.75(s, 1H), 8.6(s, 1H), 9.0(s, 1H), 10.5(br s,1H), 12.2(s, 1H); LRMS calcd 318 found [M + 1] 319 15 3,4,5,6-Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid(2,5-difluoro- phenyl)-amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 6.7(m, 1H),7.05(m, 1H), 7.75(s, 1H), 8.45(m, 1H), 8.6(s, 1H), 9.2(s, 1H), 10.0(brs, 1H), 13.4(s, 1H); Electrospray mass spectrum: m/z 339 [M − 1 163,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acidpyridin-3-ylamide H H H H 2

¹H NMR [CDCl3 + CD3OD] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 7.3(m,2H), 7.6(s, 1H), 8.3(m, 2H), 8.6(s, 1H), 8.8(s, 1H), 9.2(s, 1H) 173,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid(6-methyl- pyridin-2-yl)- amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.5(s, 3H), 2.6(t, 2H), 2.8(t, 2H),6.85(d, 1H), 7.6(t, 1H), 7.7(s, 1H), 8.2(d, 1H), 8.6(s, 1H), 9.3(s, 1H),9.6(br s, 1H) 18 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene-1-carboxylic acid (6-ethyl-pyridin- 2-yl)-amide H H H H 2

¹H NMR [CDCl3] 1.3(t, 3H), 2.3(quint, 2H), 2.6(t, 2H), 2.8(m, 4H),6.8(d, 1H), 7.5(t, 1H), 7.6(s, 1H), 8.1(d, 1H), 8.5(s, 1H), 9.2(s, 1H)19 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylicacid (5-methyl- pyridin-2-yl)- amide H H H H 2

¹H NMR [CDCl3] 2.2(s, 3H), 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H),7.4(d, 1H), 7.6(s, 1H), 8.1(s, 1H), 8.2(d, 1H), 8.5(s, 1H), 9.2(s, 1H)20 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylicacid (5-chloro- pyridin-2-yl)- amide H H H H 2

¹H NMR [CDCl3] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 7.6(dd, 1H),7.7(s, 1H), 8.3(d, 1H), 8.35(d, 1H), 8.6(s, 1H), 9.2(s, 1H), 9.7(br s,1H) 21 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylicacid benzo[1,3]dioxol- 5-ylamide H H H H 2

¹H NMR [CDCl3 + CD3OD] 2.3(quint, 2H), 2.6(t, 2H), 2.8(t, 2H), 6.0(s,2H), 6.8(d, 1H), 7.0(dd, 1H), 7.4(d, 1H), 7.6(s, 1H), 8.6(s, 1H), 9.1(s,1H) 22 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylicacid (2,3-dihydro- benzo[1,4]dioxin- 6-yl)-amide H H H H 2

Electrospray mass spectrum: m/z 363 [M − 1] 23 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (3-isopropoxy-phenyl)-amide H H H H 2

LRMS m/z 363 24 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene-1-carboxylic acid (3,4-dihydro-2H- benzo[b][1,4] dioxepin-7-yl)-amide HH H H 2

LRMS m/z 377 25 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene-1-carboxylic acid (4-phenoxy- phenyl)-amide H H H H 2

LRMS m/z 397 26 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene-1-carboxylic acid pyrazin-2-ylamide H H H H 2

LRMS calcd 306 found [M + 1] 307; ¹H NMR DMSO-d6, 2.14(m, 2H), 2.62(m,2H), 2.80(m, 2H), 7.64(s, 1H), 8.30(1H, d), 8.38(m, 1H), 8.66(s, 1H),9.04(s, 1H), 9.48(s, 1H), 11.94(bs, 1H), 13.57(s, 1H) 27 3,4,5,6-Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid(3-fluoro-4- methoxy-phenyl)- amide H H H H 2

Electrospray mass spectrum: m/z 351 [M − 1] 28 Propyl-(2-{4- [(3,4,5,6-tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carbonyl)-amino]-phenoxy}-ethyl)- carbamic acid tert-butyl ester

LRMS calcd 505 found [M + 1] 506 29 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (4-ethoxy-3- fluoro-phenyl)- amide HH H H 2

LRMS 366.39 found (M + 1) 367.3 30 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [3-fluoro-4-(2- hydroxy-ethoxy)-phenyl]-amide H H H H 2

LRMS calcd 382 found [M + 1] 31 Propyl-(2-{4- [(3,4,5,6- tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carbonyl)- amino]-phenoxy}-ethyl)-carbamic acid tert-butyl ester H H H H 2

LRMS calcd 505 found [M + 1] 506 32 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [3-fluoro-4-(2- propylamino-ethoxy)-phenyl]- amide H H H H 2

LRMS calcd 423 found [M − 1] 422 33 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [4-(2-ethylamino- ethoxy)-3-fluoro-phenyl]-amide H H H H 2

LRMS calcd 409 found [M + 1] 410 34 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid {4-[2- (cyclopropylmethyl-1-amino)-ethoxy]- 3-fluoro-phenyl}- amide H H H H 2

LRMS calcd 435 found [M + 1] 436 35 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (1-ethyl-1H- pyrazol-4-yl)- amide H HH H 2

¹H NMR (DMSO) 1.33(t, 3H), 2.11-2.20(m, 2H), 2.55-2.62(m, 2H), 2.72-2.76(m, 2H), 4.01(q, 2H), 6.5(s, 1H), 7.5(s, 1H), 7.6(s, 1H), 8.6(s,1H), 9.0(s, 1H), 11.8(brs, 1H), 12.7(brs, 1H) LCMS found (M + H) 323 363,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid(1-propyl-1H- pyrazol-3-yl)- amide H H H H 2

LCMS found (M + H) 337 37 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [3-(2-ethoxy- ethoxy)-phenyl]- amideH H H H 2

¹H NMR (DMSO) 1.21- 1.25(m, 3H), 2.25(t, 2H), 2.62(t, 2H), 2.76(t, 2H),3.57-3.61(m, 2H), 3.78-3.80(m, 2H), 4.13- 4.15(m, 2H), 6.66- 6.69(m,1H), 7.21-7.2(m., 2H), 7.54(brs, 1H), 7.66(m, 1H), 8.56(brs, 1H),9.16(brs, 1H), 12.9(s, 1H) LCMS found (M + H) 393 38 3,4,5,6-Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylic acidpyridazin-3- ylamide H H H H 2

LRMS calcd 306 found [M + 1] 307 39 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-methyl- isoxazol-3-yl)- amide H HH H 2

LCMS found (M + H) 310 40 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid quinolin-3- ylamide H H H H 2

MS found [M + H] 356.2 41 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [6-(3-isopropoxy- propylamino)-pyridin-3-yl]- amide H H H H 2

MS found [M + H] 421.3 42 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-chloro-5- methyl-pyridin-3-yl)-amide H H H H 2

MS found [M + H] 354.1 43 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-methoxy-2- methyl-pyridin-3-yl)-amide H H H H 2

MS found [M + H] 350.2 44 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-bromo-pyridin- 3-yl)-amide H H H H2

MS found [M + H] 384.1 45 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-fluoro- phenyl)-amide H H H H 2

LRMS calcd 322 found [M + 1] 323 46 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-bromo-pyridin- 3-yl)-amide H H H H2

MS found [M + H] 384.1 47 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-chloro-3- methyl-pyridin-2-yl)-amide H H H H 2

MS found [M + H] 354.1 48 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2-chloro- pyridin-3-yl)- amide H H HH 2

MS found [M + H] 340.1 49 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-chloro-2- methyl-pyridin-3-yl)-amide H H H H 2

MS found [M + H] 354.1 50 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-ethyl-6- methyl-pyridin-2-yl)-amide H H H H 2

MS found [M + H] 348.2 51 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-methyl- pyridin-3-yl)- amide H H HH 2

MS found [M + H] 320.2 52 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (4-fluoro- phenyl)-amide H H H H 2

MS found [M + H] 323.2 53 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid pyrimidin-2- ylamide H H H H 2

MS found [M + H] 307.2 54 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (4-chloro- phenyl)-amide H H H H 2

MS found [M + H] 339.1 55 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-chloro- pyridin-3-yl)- amide H H HH 2

MS found [M + H] 340.1 56 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [6-(4-methoxy- phenoxy)-pyridin-3-yl]-amide H H H H 2

MS found [M + H] 428.2 57 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3,5-dichloro- pyridin-2-yl)- amide HH H H 2

MS found [M + H] 374.1 58 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-methyl- [1,3,4]thiadiazol-2-yl)-amide H H H H 2

MS found [M + H] 327.1 59 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-methoxy- pyridin-3-yl)- amide H HH H 2

MS found [M + H] 336.2 60 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2,6-dimethoxy- pyridin-3-yl)- amideH H H H 2

MS found [M + H] 366.2 61 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2-chloro-6- methoxy-pyridin-3-yl)-amide H H H H 2

LRMS calcd 369 found [M + 1] 370 62 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2-methyl- pyridin-3-yl)- amide H H HH 2

MS found [M + H] 320.2 63 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-methyl- pyridin-2-yl)- amide H H HH 2

Electrospray mass spectrum: m/z 320 [M + 1] 64 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid [6-(2,4-dichloro-phenoxy)-pyridin- 3-yl]-amide H H H H 2

MS found [M + H] 466.2 65 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2,6-dimethyl- pyridin-3-yl)- amide HH H H 2

MS found [M + H] 334.2 66 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [6-(4- trifluoromethyl-phenoxy)-pyridin- 3-yl]-amide H H H H 2

MS found [M + H] 466.2 67 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [4-(2-ethoxy- ethoxy)-phenyl]- amideH H H H 2

¹H NMR (DMSO) 1.09-1.13 (m, 3H), 2.15(t, 2H), 2.6(t, 2H), 2.74(t, 2H),3.46-3.51(m, 2H), 3.65-3.67(m, 2H), 4.01- 4.04(m, 2H), 6.66-6.69(m, 2H),7.54(brs, 1H), 7.60-7.62(m, 2H), 8.56-8.57(brs, 1H), 11.7(brs, 1H),12.1(s, 1H) LCMS found (M + H) 393 68 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid [4-(2-isopropoxy-ethoxy)-phenyl]- amide H H H H 2

¹H NMR (DMSO) 1.08-1.09 (m, 6H), 2.15(t, 2H), 2.6(t, 2H), 2.73(t, 2H),3.58-3.61(m, 1H), 3.66(t, 2H), 4.0(t, 2H), 6.86-6.89(m, 2H), 7.54(brs,1H), 7.60-7.62(m, 2H), 8.64(s, 1H), 9.16(brs, 1H), 12.1(s, 1H) LCMSfound (M + H) 407 69 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-methyl- isoxazol-5-yl)- amide H HH H 2

LCMS found (M + H) 310 70 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-fluoro-2- methyl-phenyl)- amide HH H H 2

Electrospray mass spectrum: m/z 335 [M − 1] 71 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (5-fluoro-2-methyl-phenyl)- amide H H H H 2

Electrospray mass spectrum: m/z 324 [M + 1] 72 3,4,5,6- Tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (2-methoxy-phenyl)-amide H H H H 2

LRMS 334.38 found (M + 1) 335.2 73 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [2-(2-ethoxy- ethoxy)-phenyl]- amideH H H H 2

LRMS 392.46 found (M + 1) 393.0 74 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid 6-methyl- pyridazin-3- ylamide H H HH 2

LRMS 320.35 found (M + 1) 321.0 75 3,4,5,6- Tetrahydro-3,10- diaza-benzo[e]azulene- 1-carboxylic acid (2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6-yl)- amide H H H H 2

LCMS found (M + H) 363 76 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-ethoxy- pyridin-2-yl)- amide H H HH 2

LCMS found (M + H) 350 77 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-methoxy- pyridin-2-yl)- amide H HH H 2

LCMS found (M + H) 336 78 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid [3-(2-oxo- butoxy)-phenyl]- amide H HH H 2

LCMS found (M + H) 391 79 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-methyl-oxazol- 2-yl)-amide H H H H2

LCMS found (M + H) 310 80 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid pyridin-4-ylamide H CH₃ H H 2

LRMS 305 found (M + 1) 306 81 7-Methyl-3,4,5,6- tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (1-methyl-1H-pyrazol-3-yl)- amide H CH₃ H H 2

LRMS 322 found (M + 1) 323 82 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid pyridin-2-ylamide H CH₃ H H 2

LRMS 305 found (M + 1) 306 83 7-Methyl-3,4,5,6- tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (3-methyl-isoxazol-5-yl)- amide H CH₃ H H 2

LRMS 323 found (M + 1) 324 84 7-Methyl-3,4,5,6- tetrahydro-3,8,10-triaza- benzo[e]azulene- 1-carboxylic acid (5-methyl-isoxazol-3-yl)- amide H CH₃ H H 2

LRMS 323 found (M + 1) 324 85 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (6-methoxy-4- methyl-pyridin-3-yl)-amide H H H H 2

¹H NMR (DMSO) 2.05- 2.25(m, 5H), 2.6(t, 2H), 2.75(t, 2H), 3.80(s, 3H),6.7(s, 1H), 7.45(d, 1H), 8.25(s, 1H), 8.6(s, 1H), 9.0(s, 1H), 11.35(s,1H), 11.8(bs, 1H) 86 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2-chloro-6- methoxy-pyridin-3-yl)-amide H H H H 2

¹H NMR (DMSO) 2.1-2.2(m, 2H), 2.6(t, 2H), 2.75(t, 2H), 3.80(s, 3H),6.9(d, 1H), 7.6(s, 1H), 8.25(d, 1H), 8.65(s, 1H), 9.05(s, 1H), 11.9(bs,1H), 12.4(bs, 1H) 87 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (3-ethoxy- pyridin-2-yl)- amide H H HH 2

LRMS 349 found (M − 1) 348 88 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (2-methyl- pyrimidin-4-yl)- amide H HH H 2

LRMS 320 found (M − 1) 319 89 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (1-methyl-1H- pyrazol-3-yl)- amide HH H H 2

LRMS 308 found (M − 1) 307 90 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid (5-propyl- [1,3,4]oxadiazol-2-yl)-amide H H H H 2

¹H NMR [CDCl3 + CD3OD] 1.0(t, 3H), 1.8(qt, 2H), 2.25(m, 2H), 2.75-2.95(m, 6H), 7.7(s, 1H), 8.6(s, 1H), 9.1(s, 1H), LRMS 338 found (M − 1)337 91 3,4,5,6- Tetrahydro- 3,8,10-triaza- benzo[e]azulene- 1-carboxylicacid [1-(3- cyclobutylamino- propyl)-1H- pyrazol-3-yl]- amide H H H H 2

LRMS 405 found (M + 1) 406 92 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid pyridin-2-ylamide H H H H 2

¹H NMR [CDCl3] 2.15- 2.23(m, 2H), 2.63(t, 2H), 2.80(t, 2H), 6.98(dd,1H), 7.63-7.70(m, 2H), 8.32(dd, 1H), 8.37(dd, 1H), 8.53(s, 1H0, 9.23(s,1H), 10.73(s, 1H) 93 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid pyridin-4-ylamide H H H H 2

¹H NMR [DMSO-d6] 2.05- 2.20(m, 2H), 2.62(t, 2H), 2.78(t, 2H), 7.53(s,1H), 7.65(d, 2H), 8.42(d, 2H), 8.63(s, 1H), 9.20(s, 1H), 11.88(s, 1H) 947-Methyl-3,4,5,6- tetrahydro- 3,8,10-triaza- benzo[e]azulene-1-carboxylic acid (1-methyl-1H- pyrazol- 3-yl)-amide H Me H H 2

LRMS 322.4 found (M − 1) 321.3 95 3,4,5,6- Tetrahydro- 3,8,10-triaza-benzo[e]azulene- 1-carboxylic acid ]6-(3- diethylamino- propoxy)-pyridin-2-yl]-amide H H H H 2

LCMS found (M + H) 435

Example 81-methyl-4,5,6,7-tetrahydro-1H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester and2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester

A mixture of ethyl5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylicacid ethyl ester (100 mg, 0.362 mmol) and methyl hydrazine (83 mg, 1.81mmol) in EtOH (2 mL) is stirred at 100° C. for 3 h. After cooling, thereaction mixture is diluted with CH₂Cl₂ and washed with half saturatedaq NaHCO₃ (10 mL), H₂O (10 mL), and brine (10 mL). The CH₂Cl₂ extract isdried over Na₂SO₄ and concentrated. The crude material is purified byflash chromatography on silica gel. Elution with 3:1 EtOAc-hexanes(+0.5% Et₃N) followed by 100% ethyl acetate (+0.5% Et₃N) separated thetwo regioisomers. Early fractions: 23 mg (25%) of1-methyl-4,5,6,7-tetrahydro-1H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester; electrospray mass spectrum:m/z 260 [M+1]; ¹H NMR (CDCl₃, 400 MHz) δ9.32 (br s, 1H), 7.39 (d, J=2.8Hz, 1H), 7.37 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 2.54 (m,2H), 2.46 (m, 2H), 2.10 (m, 2H), 1.31 (t, J=7.2 Hz, 3H). Laterfractions: 69 mg (74%) of2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester; electrospray mass spectrum: m/z 260 [M+1]; ¹H NMR(CDCl₃, 300 MHz) δ8.42 (br s, 1H), 7.20 (d, J=3.0 Hz, 1H), 7.05 (s, 1H),4.29 (q, J=7.2 Hz, 2H), 3.82 (s, 3H), 2.82 (m, 2H), 2.67 (m, 2H), 1.96(m, 2H), 1.32 (t, J=7.2 Hz, 3H).

Example 92-Methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid (2-fluoro-phenyl)-amide

To a solution of 2-fluoroaniline (103 mg, 0.926 mmol) in CH₂Cl₂ (2.0 mL)at 0° C. under N₂ is slowly added AlMe₃ (0.46 mL, 2.0 M in toluene). Theresulting solution is stirred at room temperature for 1 h. Next,2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester (60 mg, 0.231 mmol) is added in one portion. Theresulting mixture is then stirred at reflux for 2 h. After cooling, thereaction mixture is carefully diluted with saturated aq NH₄Cl (˜5 mL)and some H₂O. The mixture is stirred vigorously for 30 min. and thenextracted three times with CH₂Cl₂(containing some (˜5%) MeOH). Thecombined extracts are dried over K₂CO₃ and concentrated. The crudematerial is purified by flash chromatography on silica gel. Elution with40:1 CHCl₃-MeOH followed by 30:1 CHCl₃-MeOH and finally 20:1 CHCl₃-MeOHafforded, after concentration of the fractions containing pure product,a residue, which is then granulated with Et₂O. The suspension isfiltered, and the solid washed with Et₂O and dried, affording 45 mg(60%) of2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid (2-fluoro-phenyl)-amide as an off-white solid. Electrospray massspectrum: m/z 325 [M+1].

Example 101-Methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid (2-fluoro-phenyl)-amide

The title compound is prepared according to Example 9 using2-fluoroaniline and1-methyl-4,5,6,7-tetrahydro-1H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester. Electrospray mass spectrum: m/z 325 [M+1].

Example 114,5,6,7-Tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester

The title compound is prepared in analogous fashion to Example 8 using5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylicacid ethyl ester and hydrazine acetate. The crude product mixture iscarried into the next step without purification. Electrospray massspectrum: m/z 246 [M+1]; ¹H NMR (DMSO-d₆, 300 MHz) δ>13.0 (br s, 1H),11.65 (br s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 4.25 (q, J=7.2 Hz, 2H),2.91 (m, 2H), 2.76 (m, 2H), 1.84 (m, 2H) 1.28 (t, J=7.2 Hz, 3H).

Example 12 Preparation of4,5,6,7-Tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid (2-fluoro-phenyl)-amide

Step 1:

5,6-Dihydro-4H-1,2,7-triaza-cyclopenta[e]azulene-2,7,9-tricarboxylicacid 2,7-di-tert-butyl ester 9-ethyl ester is prepared by the proceduredescribed in Example 8, using4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester, 2.3 eq of Boc₂O, and 2.5 eq of Et₃N. Electrospray massspectrum: m/z 446 [M+1]; ¹H NMR (CDCl₃, 300 MHz) δ7.77 (s, 1H), 7.62 (s,1H), 4.35 (q, J=7.2 Hz, 2H), 3.26 (m, 2H), 2.68 (m, 2H), 1.99 (m, 2H),1.61 (s, 9H), 1.59 (s, 9H), 1.33 (t, J=7.2 Hz, 3H).

Step 2:

To a solution of 2-fluoroaniline (202 mg, 1.82 mmol) in CH₂Cl₂ (4.0 mL)at 0° C. under N₂ is slowly added AlMe₃ (0.91 mL, 2.0 M in toluene). Theresulting solution is stirred at room temperature for 1 h. Next,5,6-dihydro-4H-1,2,7-triaza-cyclopenta[e]azulene-2,7,9-tricarboxylicacid 2,7-di-tert-butyl ester 9-ethyl ester (162 mg, 0.364 mmol) is addedin one portion. The resulting mixture is then stirred at reflux for 2 h.After cooling, the reaction mixture is carefully diluted with saturatedaq NH₄Cl (˜5 mL) and some H₂O. The mixture is stirred vigorously for 30min. and then extracted three times with CH₂Cl₂(containing some (˜5%)MeOH). The combined extracts are dried over K₂CO₃ and concentrated. Thecrude material is purified by flash chromatography on silica gel,affording 102 mg (68%) of an amide product containing only one Bocgroup. ¹H NMR (CDCl₃, 300 MHz) δ8.52 (td, J=8.1, 1.4 Hz, 1H), 8.06 (s,1H), 7.36 (s, 1H), 7.18-7.03 (m, 3H), 3.37 (m, 2H), 2.79 (m, 2H), 2.03(m, 2H), 1.62 (s, 9H). This product is then dissolved in 4 mL of EtOHand 1 mL of conc. aq HCl. The solution is stirred at room temperatureovernight and at 90° C. for 3 h. The reaction mixture is thenconcentrated under a stream of N₂ to afford a solid, which is thensuspended in H₂O and filtered. The solid is thoroughly washed with H₂Oand Et₂O to afford, after drying, 34 mg (44%) of4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid (2-fluoro-phenyl)-amide as a light yellow/off-white solid.Electrospray mass spectrum: m/z 311 [M+1].

Example 12a2-(2-Diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid [1,3,4]thiadiazol-2-ylamide

Step 1:

A solution of2-(2-Hydroxy-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester (866 mg, 2.99 mmol) in CH₂Cl₂(6 mL) at 0° C. under N₂is treated with pyridine (0.73 mL, 8.98 mmol) followed bymethanesulfonyl chloride (0.28 mL, 3.59 mmol). The reaction mixture isstirred at 0° C. for 10 min. and at room temperature for 4 h. Thereaction mixture is then concentrated in vacuo. The crude2-(2-methanesulfonyloxy-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester is used without further purification. Electrospray massspectrum: m/z 366 [M−1].

Step 2:

To a solution of2-(2-methanesulfonyloxy-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester (158 mg, 0.43 mmol) in CH₃CN is added excessdiethylamine (>3 eq) and excess K₂CO₃. The reaction mixture is stirredovernight at 83° C. in a sealed tube. The reaction mixture is thenextracted with CH₂Cl₂ and washed with water. The aqueous wash is thenextracted twice more with CH₂Cl₂. The combined extracts are dried overK₂CO₃ and concentrated. The crude material is purified by flashchromatography on silica gel, affording 107 mg (72%) of2-(2-diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester. Electrospray mass spectrum:m/z 343 [M−1]; ¹H NMR (CDCl₃, 300 MHz) δ8.78 (br, 1H), 7.17 (d, J=2.7Hz, 1H), 7.15 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.12 (t, J=7.2 Hz, 2H),2.91 (m, 2H), 2.81 (m, 2H), 2.65 (m, 2H), 2.59 (q, J=7.2 Hz, 4H), 1.94(m, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 6H)

Step 3:

To a mixture of 2-amino-1,3,4-thiazole (81 mg, 0.798 mmol) in CH₂Cl₂(2mL) at 0° C. under N₂ is added 2.0 M trimethylaluminum in toluene (0.4mL, 0.798 mmol). The mixture is then stirred at room temperature for 1hr. To the resulting solution is added a solution of2-(2-diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester (55 mg, 0.16 mmol) in CH₂Cl₂(1.0 mL) via cannula,followed by a 0.5 mL rinse. The reaction mixture is then stirred atreflux for 4 h. After cooling, the reaction mixture is quenched by theaddition of a small amount of 2.0 M aq NaOH and water. A small amount ofMeOH is added, and the resulting mixture is stirred vigorously for 30min. The mixture is filtered through a pad of Celite, washing withCH₂Cl₂ containing some (˜5%) MeOH. The filtrate is concentrated, and theresidue is purified by preparative thin-layer chromatography (silicagel). Two developments using 20:1 CHCl₃-MeOH (+1% triethylamine) affords53 mg (83%) of2-(2-diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid [1,3,4]thiadiazol-2-ylamide as an off-white solid. Electrospraymass spectrum: m/z 398 [M−1]; ¹H NMR (CDCl₃, 300 MHz) δ9.14 (br, 1H),8.79 (s, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.26 (d, J=0.6 Hz, 1H) 4.37 (m,2H), 3.06 (m, 2H), 3.00 (m, 2H), 2.79 (m, 2H), 2.61 (q, J=7.2 Hz, 4H),1.97 (m, 2H), 0.99 (t, J=7.2 Hz, 6H) The solid is dissolved in 3-4 mL ofEtOH and treated with ˜3 eq of 1.0 M HCl in Et₂O. The solution isstirred for 10 min. and then concentrated to remove most of the EtOH.Methyl tert-butyl ether is added, and the resulting precipitate isgranulated and filtered. The solid is washed with Et₂O and dried under astream of N₂ to afford 54 mg (77%) of the hydrochloride salt of2-(2-diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylicacid [1,3,4]thiadiazol-2-ylamide. Electrospray mass spectrum: m/z 398[M−1]; ¹H NMR (CD₃OD, 300 MHz) δ11.32 (br, 1H), 9.22 (s, 1H), 7.67 (d,J=3.0 Hz, 1H), 7.64 (s, 1H), 4.71 (m, 2H), 4.02 (m, 2H), 3.37 (q, J=7.2Hz, 4H), 3.05 (m, 2H), 2.85 (m, 2H), 1.99 (m, 2H), 1.33 (t, J=7.2 Hz,6H).

Example 12b

Using the method shown in Scheme 6 and further illustrated in Examples8-12 the compounds shown in Table 4 were prepared.

TABLE 4

Cpd Spectral # Name R^(A) R⁴ R⁵ R⁶ k Ar Data 1 2-Methyl-4,5,6,7-tetrahydro-2H- 1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid(2-fluoro- phenyl)-amide CH₃ H H H 2

MS m/z [M + 1] 325 2 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid pyridin-3- ylamide CH₃ H H H 2

MS m/z [M + 1] 308 3 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid pyrazin-2- ylamide CH₃ H H H 2

MS m/z [M + 1] 309 4 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(2,3- dihydro- benzo[1,4]dioxin-6-yl)-amide CH₃ H H H 2

MS m/z [M + 1] 365 5 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(4-ethoxy- phenyl)-amide CH₃ H HH 2

MS m/z [M − 1] 349 6 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(3-fluoro-4- methoxy-phenyl)-amide CH₃ H H H 2

MS m/z [M − 1] 353 7 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(5-methyl- pyridin-2-yl)- amideCH₃ H H H 2

MS m/z [M − 1] 320 8 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(5-methyl- isoxazol-3-yl)- amideCH₃ H H H 2

MS m/z [M − 1] 310 9 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid[3-(2- ethoxy-ethoxy)-phenyl]-amide CH₃ H H H 2

MS m/z [M + 1] 395 10 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid[4-(2- ethoxy-ethoxy)-phenyl]-amide CH₃ H H H 2

MS m/z [M + 1] 395 11 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6-yl)- amide CH₃ H H H 2

MS m/z [M + 1] 366 12 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(2,6-dimethoxy- pyridin-3-yl)-amide CH₃ H H H 2

MS m/z [M + 1] 368 13 (R)-2-Methyl- 4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid[4- (tetrahydro-furan-3-yloxy)- phenyl]-amide CH₃ H H H 2

MS m/z [M + 1] 393 14 (S)-2-Methyl- 4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid[4- (tetrahydro-furan-3-yloxy)- phenyl]-amide CH₃ H H H 2

MS m/z [M + 1] 393 15 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid[4-(3- methyl-oxetan-3-ylmethoxy)- phenyl]-amide CH₃ H H H 2

MS m/z [M + 1] 409 16 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid [1,3,4]thiadiazol- 2-ylamide CH₃H H H 2

MS m/z [M + 1] 329 17 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(2-methoxy- pyridin-3-yl)- amideCH₃ H H H 2

MS m/z [M + 1] 338 18 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid o-tolylamide CH₃ H H H 2

MS m/z [M + 1] 321 19 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid pyridin-2- ylamide CH₃ H H H 2

MS m/z [M + 1] 308 20 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(5-ethoxy- pyridin-2-yl)- amideCH₃ H H H 2

MS m/z [M + 1] 352 21 2-Methyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid(5-methoxy- pyridin-2-yl)- amideCH₃ H H H 2

MS m/z [M + 1] 338 22 2-(2-Hydroxy- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid pyridin-3-ylamide

H H H 2

MS m/z [M − 1] 336 23 2-Ethyl-4,5,6,7- tetrahydro-2H- 1,2,7-triaza-cyclopenta[e]azulene- 9-carboxylic acid pyridin-3-ylamide

H H H 2

MS m/z [M − 1] 320 24 2,3-Dimethyl- 4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid(1-methyl-1H-pyrazol-3- yl)-amide CH₃ CH₃ H H 2

MS m/z [M − 1] 323.3 25 2,3-Dimethyl- 4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid pyrazin-2- ylamideCH₃ CH₃ H H 2

MS m/z [M + 1] 321.3 26 2-(2-Ethylamino- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid pyridin-3- ylamide

H H H 2

MS m/z [M − 1] 363 27 2-(2-Ethylamino- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid(1-methyl-1H-pyrazol-3-yl)- amide

H H H 2

MS m/z [M − 1] 366 28 2-(2-Ethylamino- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid[1,3,4]thiadi-azol-2-ylamide

H H H 2

MS m/z [M − 1] 370 29 2-(2- Diethylamino- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid(1-methyl-1H-pyrazol-3-yl)- amide

H H H 2

MS m/z [M − 1] 394 30 2-(2- Diethylamino- ethyl)-4,5,6,7- tetrahydro-2H-1,2,7-triaza- cyclopenta[e]azulene- 9-carboxylic acid[1,3,4]thiadi-azol-2-ylamide

H H H 2

MS m/z [M − 1] 398

Example 134,5,6,7-Tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester

In a sealedtube,4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (2.6 mmol) andtris(dimethylamino)methane (5.2 mmol) are combined and heated at 60° C.for 3 hours. After cooling to RT the volatile material is removed invacuo. To the residue were added hydroxylamine hydrochloride (7.8 mmol)and 7 mL EtOH. The mixture is heated at 100° C. for 16 hours. Thesolvent is evaporated in vacuo and the residue is taken up in CH₂Cl₂ andwashed two times with NaHCO₃ (aq). The organic layer is dried overNa₂SO₄ and evaporated in vacuo and the residue chromatographed using 10%MeOH in CH₂Cl₂ as mobile phase to yield4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester as a white solid (76%). ¹H NMR (CDCl₃) 1.19 (t, 3H),1.95-2.07 (m, 2H), 2.78 (t, 2H), 2.95 (t, 2H), 4.38 (q, 2H), 7.26 (s,1H), 8.03 (s, 1H), 8.77 (s, 1H).

Example 143-Methyl-4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester

In a sealed tube were5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and hydroxylaminehydrochloride (2.2 mmol) and 10 mL EtOH. The mixture is heated at 100°C. for 16 hours. The solvent is evaporated in vacuo and the residue istaken up in CH₂Cl₂ and washed two times with NaHCO₃ (aq). The organiclayer is dried over Na₂SO₄ and evaporated in vacuo and the residuechromatographed using 10% MeOH in CH₂Cl₂ as mobile phase to yield3-methyl-4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylicacid ethyl ester as a white solid (76%). ¹H NMR (CDCl₃+CD₃OD) 1.3 (t,3H), 1.90-1.98 (m, 2H), 2.10 (s, 3H), 2.35 (t, 2H), 2.75-2.82 (m, 2H),4.21 (q, 2H), 7.15 (s, 1H)

Example 14a

Using the method shown in Scheme 7 and further illustrated in Examples13-14 the compounds shown in Table 5 were prepared.

TABLE 5

Cpd# Name R4 R5 R6 k Ar Spectral Data 1 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid phenyl-amide HH H 2

LRMS calcd 293.32 found (M + 1) 294 2 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(3-methoxy-phenyl)- amide H H H 2

LRMS calcd 323.3 found (M + 1) 324 3 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6- yl)amide H H H 2

LRMS calcd 351.3 found (M + 1) 352.3 4 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(4-methoxy-phenyl)- amide H H H 2

LRMS calcd 323.3 found (M − 1) 322 5 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid[4-(2-propylamino- ethoxy)-phenyl]- amide H H H 2

LRMS calcd 394.4 found (M + 1) 395 6 Propyl-(2-{4- [(4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]-azulene- 9-carbonyl)-amino]-phenoxy}- ethyl)-carbamic acid tert-butyl ester H H H 2

LRMS calcd 494.59 found (M − 1) 493.3 7 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]-azulene- 9-carboxylic acid(5-ethoxy-pyridin-2- yl)amide H H H 2

LRMS calcd 338.36 found (M + 1) 339 8 4,5,6,7-Tetrahydro-1-oxa-2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acidpyridin-3-ylamide H H H 2

LRMS calcd 294.3 found (M + 1) 295.3 9 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(4-methoxy-phenyl)- amide CH₃ H H 2

LRMS calcd 337.4 found (M + 1) 338 10 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(5-ethoxy-pyridin-2- yl)-amide CH₃ H H 2

LRMS calcd 352.4 found (M + 1) 353 11 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid2-(5-methyl- [1,3,4]thiadiazol-2- yl)-amide CH₃ H H 2

LRMS calcd 329.4 found (M + 1) 330 12 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(5-methyl-isoxazol- 3-yl)-amide CH₃ H H 2

LRMS calcd 312.3 found (M + 1) 313 13 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acidpyridin-2-ylamide CH3 H H 2

LRMS calcd 308.3 found (M + 1) 309 14 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acidpyrazin-2-ylamide CH3 H H 2

LRMS calcd 309.3 found (M + 1) 310 15 3-Methyl-4,5,6,7-tetrahydro-1-oxa- 2,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid(6-methyl-pyridin-2- yl)-amide CH3 H H 2

LRMS calcd 322.3 found (M + 1) 323

Example 15 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylicacid ethyl ester

Step 1:

To a mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acidethyl ester (2.4 mmol) in 10 mL 1,4-dioxane is added di-tert-butyldicarbonate (2.9 mmol), followed by a solution of K₂CO₃ (2.9 mmol) in 5mL H₂O. After stirring at RT for 16 hours 50 mL ethyl acetate and 50 mLH₂O are added to the mixture. The organic layer is separated and theaqueous layer is extracted several times with EtOAc. The organic layersare combined, dried over Na₂SO₄ and evaporated in vacuo yielding4-Oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester, 700 mg, as a dark yellow/brown oil (95%). ¹H NMR (CDCl₃)1.38 (t, 3H), 1.62 (s, 9H), 2.11-2.19 (m, 2H), 2.50-2.58 (m, 2H), 3.17(t, 2H), 4.37 (q, 2H), 7.70 (s, 1H).

Step 2:

To the solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (33 mmol) in 140 mL THF is addeddropwise a solution of phenyltrimethylammonium bromide (33 mmol) in 56mL THF. After stirring at RT for an additional 1½ hours the mixture ispoured onto 200 mL 5% NaHCO₃ solution, and is then extracted severaltimes with EtOAc. The organic layers are combined, dried over Na₂SO₄ andevaporated in vacuo. The dark brown oil is chromatographed using ethylacetate 1:hexanes 10 as a mobile phase to yield5-bromo-4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester, 5 g, as a white solid (40%). ¹H NMR(CDCl₃)1.39 (t, 3H), 1.62 (s, 9H), 2.42-2.51 (m, 2H), 3.20-3.38 (m, 2H),4.35 (q, 2H), 4.58 (t, 1H), 7.79 (s, 1H)

Step 3:

To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.78 mmol) in 10mL CH₃OH is added thioacetamide (1.55 mmol). After stirring underrefluxing for 16 hours the solvent is removed in vacuo. The brown oil ischromatographed using EtOAc 1: hexane 1, followed by 5% MeOH in CH₂Cl₂as mobile phases to yield2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethylester as a white solid (34%). ¹H NMR (DMSO-d₆) 1.27 (t, 3H), 2.60 (s,3H), 2.78(t, 2H), 2.96 (t, 2H), 4.19 (q, 2H), 7.21 (s, 1H), 11.44 (s,1H).

Example 16 2-Ethyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylicacid ethyl ester

The title compound is prepared by reacting5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester with thiopropionamide essentiallyaccording to the procedures described in Example 15, Step 3. ¹H NMR(CDCl₃) 1.33-1.42 (m, 6H), 2.80-2.90 (m, 2H), 2.98-3.10 (m, 4H), 2.37(q, 2H), 7.24 (s, 1H), 8.60 (s, 1H).

Example 17 2-Methyl-3,4,5,6-tetrahydro-imidazo[4,5-e]indole-8-carboxylicacid ethyl ester

To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.66 mmol) in 15mL 1,4-dioxane is added acetamidine hydrochloride (3.32 mmol). Afterstirring under refluxing for 16 hours the solvent is removed in vacuo.To the residue is added 14 mL CHCl₃ and 2 mL MeOH and the mixture isstirred for 10 min. The solid is filtered off. The mother liquid isconcentrated and is chromatographed using 10% MeOH in CH₂Cl₂ as mobilephase to yield2-methyl-3,4,5,6-tetrahydro-imidazo[4,5-e]indole-8-carboxylic acid ethylester as a white solid (30%). ¹H NMR (DMSO-d₆) 1.30 (t, 3H), 2.28 (s,3H), 2.70 (t, 2H), 2.79 (t, 2H), 4.22 (q, 2H), 7.20 (s, 1H), 10.58 (s,1H), 11.43 (s, 1H).

Example 182-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta-[e]azulene-9-carboxylicacid methyl ester

Step 1:

To a solution of4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole1,3-dicarboxylic acid3-methyl ester 1-tert-butyl ester(l.1 g, 3.6 mmol) in DMSO(20 mL) isadded 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wisewith the aid of a cooling bath and the resulting mixture is stirred for18 h at RT. Water is added and the reaction mixture is extracted withether . The combined ether layers are washed with saturated brine, driedover Na₂SO₄, and concentrated in vacuo. The residue is purified by flashchromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield915 mg of5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). ¹HNMR(CDCl₃) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58(m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m,1H), 7.79 (s, 1H)

Step 2:

A mixture of5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol),4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO₃(813 mg,9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT,MeOH(5 mL) is added and the mixture is filtered. The filtrate isconcentrated in vacuo and the brown residue is purified by flashchromatography on silica gel (10% MeOH/CH₂Cl₂) to yield 197 mg of2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylicacid methyl ester as a yellow solid (53%). ¹H NMR (CDCl₃) 2.06 (quint,2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d,2H) 8.28 (br s, 1H) 8.56 (d, 2H)

Example 192-Pyridin-4-yl-4,5,6,7-tetrahydrdo-3H-1,3,7-triaza-cyclopenta[e]-azulene-9-carboxylicacid phenyl amide

To a solution of Aniline(155 L, 1.7 mmol) in CH₂Cl₂(5 mL) at RT is addedTrimethylaluminum(0.85 mL of 2M solution in toluene, 1.7 mmol) and themixture is stirred for 30 min. To this is added a solution of2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylicacid methyl ester(51 mg, 0.17 mmol) in CH₂Cl₂(2 mL) and the mixture isrefluxed for 18 h and diluted with CH₂Cl₂. MeOH(5 mL) is added slowlywith vigorous stirring. The mixture is filtered through celite,concentrated in vacuo, and purified by flash chromatography on silicagel to yield 20 mg of2-Pyridin-4-yl-4,5,6,7-tetrahydrdo-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylicacid phenyl amide as a yellow solid(32%). LRMS calcd 369.43 found (M+H)370.07

Example 202-Methyl-4,5,6,7-tetrahydro-3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylicacid methyl ester

A mixture of5-Bromo-4-oxo-5,6,7,8-tetrahydro-4-H-cyclohepta[b]pyrrole-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester(880 mg, 2.27 mmol) andThioacetamide(426 mg, 4.54 mmol) in MeOH(20 mL) is refluxed for 20 h andconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel (50% EtOAc/Hex to 10% MeOH/CH₂Cl₂) to yield 382 mg of2-Methyl-4,5,6,7-tetrahydro-3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylicacid methyl ester as a yellow foam(64%). ¹H NMR (CD₃OD) 2.18 (quint,2H), 2.61 (s, 3H), 2.70 (t, 2H) 2.78 (t, 2H), 3.73 (s, 3H), 7.29 (s, 1H)

Example 21

Using the method shown in Scheme 8 and further illustrated in Examples15-20 the compounds shown in Table 6 were prepared.

TABLE 6

Cpd# Name X R4 R5 R6 k Ar Spectral Data 1 2-Methyl-4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylicacid(4-imidazol- 1-ylmethyl- phenyl)-amide S CH₃ H H 2

LRMS calcd 403.5 found (M + 1) 404.1 2 2-Methyl-4,5,6,7- tetrahydro-3-thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid[4-(2-ethylamino- ethoxy)-phenyl]- amide S CH₃ H H 2

LRMS calcd 410.54 found (M + 1) 411.3 3 2-Methyl-4,5,6,7- tetrahydro-3-thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylic acid[4-(2-propylamino- ethoxy)-phenyl]- amide S CH₃ H H 2

LRMS calcd 424.57 found (M − 1) 423.2 4 Ethyl-(2-{4-[(2- methyl-4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carbonyl)-amino]phenoxy}- ethyl)-carbamic acid tert-butyl ester S CH₃ H H 2

LRMS calcd 510.66 found (M − 1) 509.4 5 (2-{4-[(2-Methyl- 4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carbonyl)-amino]-phenoxy}- ethyl)-propyl- carbamic acid tert-butyl ester S CH₃ H H2

LRMS calcd 524.68 found (M − 1) 523.2 6 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid phenylamide S CH₃ H H 1

LRMS calcd 309.39 found (M + 1) 310.88 7 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid [4-(3-imidazol-1- yl-propoxy)-phenyl]-amide S CH₃ H H 1

LRMS calcd 433.53 found (M + 1) 434.03 8 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid [4-(2-imidazol-1- yl-ethyl)-phenyl]-amide S CH₃ H H 1

LRMS calcd 403.51 found (M + 1) 404.0 9 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid [4-(2-imidazol-1- yl-ethoxy)-phenyl]-amide S CH₃ H H 1

LRMS calcd 419.51 found (M + 1) 420.0 10 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid (4- [1,2,4]triazol-1-ylmethyl-phenyl)- amide S CH₃ H H 1

LRMS calcd 390.47 found (M + 1) 391.1 11 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid (4-imidazol-1-ylmethyl-phenyl)- amide S CH₃ H H 1

LRMS calcd 389.48 found (M + 1) 390.1 12 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid (1H- benzoimidazol-5-yl)-amide S CH₃ H H 1

LRMS 349.42 found (M + 1) 350.2 13 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid [3-fluoro-4-(2-morpholin-4-yl- ethoxy)-phenyl]- amide S CH₃ H H 1

LRMS calcd 456.54 found 456.85 14 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid {4-[2-(4-benzyl-piperidin-1-yl)- ethoxy]-phenyl}- amide S CH₃ H H 1

LRMS calcd 526.70 found 527.1 15 2-Methyl-5,6- dihydro-4H- thiazolo[4,5-e]indole-8-carboxylic acid [3-fluoro-4-(2- pyrrolidin-1-yl-ethoxy)-phenyl]- amide S CH₃ H H 1

LRMS calcd 440.54 found 440.9 16 2-Methyl-5,6- dihydro-4H- thiazolo[4,5-e]indole-8- carboxylic acid [4-(2- propylamino- ethoxy)-phenyl]- amide SCH₃ H H 1

LRMS calcd 410.54 found (M + 1) 411.0 17 2-Methyl-5,6- dihydro-4H-thiazolo[4,5- e]indole-8- carboxylic acid [4-(1-benzyl-1H- imidazol-2-ylmethoxy)- phenyl]-amide S CH₃ H H 1

LRMS calcd 496.59 found 497.03 18 2-Ethyl-5,6- dihydro-4H- thiazolo[4,5-e]indole-8- carboxylic acid phenylamide S Et H H 1

LRMS calcd 323.42 found 323.93 19 2-Methyl-3,4,5,6- tetrahydro-imidazo[4,5- e]indole-8- carboxylic acid phenylamide NH CH₃ H H 1

LRMS calcd 292.34 found (M − 1) 291.0 20 2-Methyl-4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylic acidphenylamide NH CH₃ H H 2

LRMS calcd 306.37 found (M + H) 307.30 21 2-Methyl-4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylicacid(4-methoxy- phenyl)amide NH CH₃ H H 2

LRMS calcd 336.39 found (M + H) 337.07 22 2-Methyl-4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylicacid(2-fluoro- phenyl)-amide NH CH₃ H H 2

LRMS calcd 324.35 found (M + H) 325.40 23 2-Methyl-4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylicacid(6-methoxy- pyridin-3-yl)- amide NH CH₃ H H 2

LRMS calcd 337.38 found (M + H) 338.07 24 2-Cyclopropyl- 4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylic acidphenylamide NH

H H 2

LRMS calcd 332.41 found (M + H) 333.06 25 2-Methyl-4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e]azulene- 9-carboxylicacid(4-ethoxy- phenyl)-amide NH CH₃ H H 2

LRMS calcd 350.41 found (M + H) 351.08 26 2-Pyridin-4-yl- 4,5,6,7-tetrahydro-3H- 1,3,7-triaza- cyclopenta[e] azulene-9- carboxylic acid(4-methoxy- phenyl)-amide NH

H H 2

LRMS calcd 399.39 found (M + H) 400.09 27 2-Methyl-4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylic acidphenylamide S CH₃ H H 2

LRMS calcd 323.42 found (M + H) 324.30 28 2-Methyl-4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylicacid(4-methoxy- phenyl)-amide S CH₃ H H 2

LRMS calcd 353.44, found (M + H) 354.02 29 2-Pyridin-4-yl- 4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e] azulene-9- carboxylic acidphenylamide S

H H 2

LRMS calcd 386.48 found (M + H) 387.03 30 2-Pyridin-4-yl- 4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e] azulene-9- carboxylic acid(4-methoxy- phenyl)-amide S

H H 2

LRMS calcd 416.50 found (M + H) 417.03 31 2-Methyl-4,5,6,7-tetrahydro-3- thia-1,7-diaza- cyclopenta[e]azulene- 9-carboxylicacid(1-methyl- 1H-pyrazol-3-yl)- amide S CH₃ H H 2

LRMS calcd 327 found (M + H) 328

Example 21a Preparation of4,5,6,7-tetrahydro-1,3a,7-triaza-cyclopenta[e]azulene-9-carboxylic acidpyrazin-2-ylamide

Step 1:

A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid propylester (2.0 g) and NaN₃ (2.0 g) in 50 mL of trifluoroacetic acid isstirred at 60-80° C. for a period of 3 days during which additional 2.5g NaN₃ of is added on first, second and third day. After diluted withwater, the mixture is extracted with Ethyl acetate. The extract iswashed with NaHCO₃, brine and concentrated under reduced pressure. Theresidue is subject to a silica gel chromatography eluting with 10% MeOHin CH₂Cl₂ to give 500 mg of4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acidpropyl ester as a foam.

Step 2:

A mixture of compound (500 mg) from Step 1 and P₄S₁₀ (2.0 g) in 20 mL ofpyridine is heated at 80° C. with stirring overnight. It is cooled andevaporated under vacuum, then diluted with water and stirred. Theinsoluble material is filtered and the mother liquid is extracted withCH₂Cl₂/EtOAc (1:4). The combined extract is washed with brine, dried andconcentrated to give 120 mg of4-thioxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acidpropyl ester.

Step 3:

A mixture of compound (120 mg) from Step 2, Hg(OAc)₂(160 mg) and2,2-dimethoxy-ethylamine (0.5 mL) in 5 mL of THF is stirred at roomtemperature for 2 hours. The volatiles are removed under vacuum. Theresidue is dissolved in 15 mL of MeOH and 1 mL of 37% HCl. The resultantmixture is heated at 50° C. overnight. It is cooled and evaporated undervacuum, then diluted with MeOH and CH₂Cl₂(2:1). The mixture is filteredthrough celite. The mother liquid is concentrated to a residue to whichare added ethyl acetate, water and K₂CO₃. The organic layer is separatedand concentrated to a solid (57 mg) as4,5,6,7-tetrahydro-1,3a,7-triaza-cyclopenta[e]azulene-9-carboxylic acidpropyl ester.

Step 4:

To a stirred solution of aminopyrazine (100 mg) in 5 mL ofdichloroethane is added a solution of AlMe₃ in toluene (2 M, 0.5 mL)under nitrogen. The mixture is stirred at room temperature for 1 hour.25 mg of compound from Step 3 is added once. The resultant mixture isheated at 60° C. overnight. It is cooled and quenched with water, anddiluted with CH₂Cl₂. The organic layer is separated and washed withbrine, dried and concentrated. The residue is subject to a silica gelplate chromatography eluting with 10% MeOH in CH₂Cl₂ yields 5 mg of4,5,6,7-tetrahydro-1,3a,7-triaza-cyclopenta[e]azulene-9-carboxylic acidpyrazin-2-ylamide.

Example 21b Preparation of 2-methoxy-7H-pyrrolo[2,3-c][1,5]naphthyridine 9-carboxylic acid-pyridin-2-ylamide

Step 1:

A mixture of 15.4 g (0.1 mol) of 6-methoxy-3-nitropyridine and 20.4 g(0.1 mol) of 1-chloromethane-sulfonyl-4-methyl-benzene is dissolved in100 mL of DMF and cooled to 5 C. To this solution is added, dropwise,100 mL (0.1 mol) of a 1M solution of potassium t-butoxide in THF,keeping the temperature≦10 C. The dark reaction mixture is stirred for18 hours at room temperature. The reaction mixture is evaporated toremove the THF, and to the remaining solution is added 100 mL of water.A dark brown precipitate formed which is collected by filtration. Thissolid is triturated with isopropyl ether for 1 hour and refiltered toyield 12 grams of6-methoxy-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine. ¹H NMR (CDCl₃)δ8.25 (d, 1H), 7.60 (m, 2H), 7.30 (m, 2H), 6.80 (d, 1H), 5.10 (s, 1H),3.75 (s, 3H), 2.40 (s, 3H). Mass Spectrum: m/e=323.1 (p+1), TLC (CDCl₃)Rf=0.45

Step 2:

A mixture of 5.0 g (15.5 mmol) of6-methoxy-3-nitro-2-(toluene-4-sulfonyl methyl)-pyridine and 1.8 mL (16mmol) of ethyl bromoacetate is dissolved in 20 mL of DMF. To thissolution is added 4.4 g (32 mmol) of K₂CO₃ and the reaction mixture isheated to 50° C. for 18 hours. The reaction mixture is cooled to roomtemperature and diluted with 300 mL of water. The mixture is extractedwith ethyl acetate. The ethyl acetate extracts are dried (Na₂SO₄) andevaporated to yield 7.2 grams of6-methoxy-3-nitro-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethylester. ¹H NMR (CDCl₃) δ8.30 (d, 1H), 7.60 (d, 2H), 7.30 (d, 2H), 6.80(d, 1H), 6.30 (m, 1H), 4.0 (q, 2H), 3.80 (s, 3H), 3.60 (m, 1H), 3.10 (m,1H), 2.40 (s, 3H), 1.10 (t, 3H). Mass spectrum: m/e=409.0 (p+1). TLC(7/3: hexanes/ethyl acetate) Rf=0.5.

Step 3:

To a solution of 10.2 grams (0.0259 mol) in 500 mL of ethanol is addedapproximately 1 gram of Raney Nickel. The mixture is hydrogenated at 40psi for 18 hours. The mixture is filtered and the solvent evaporated toyield 9.45 grams of[3-amino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl-acetic acid ethylester. ¹H NMR (CDCl₃) δ7.4-7.8 (m, 5H), 7.10 (m, 1H), 6.5 (m, 1H), 5.2(m, 1H), 4.0 (q, 2H), 3.25 (s, 3H) 3.0-3.2 (m, 2H), 1.1 (s, 3H). Massspectrum: m/e=365.3 (p+1) TLC (7/3: hexanes/ethyl acetate) Rf−0.4.

Step 4:

To a solution of 9.45 g (0.026 m) of[3-amino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethylester dissolved in 150 mL of methylene chloride is added 150 mL ofsaturated sodium bicarbonate followed by 5.56 mL (0.038 m) ofcarbo-benzyloxy chloride. The reaction mixture is stirred for 20 hoursat room temperature. The water layer is separated from the organic layerand the organic layer is dried (Na₂SO₄) and evaporated to yield 15.73grams of[3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-aceticacid ethyl ester as a yellow solid. ¹H NMR (CDCl₃) δ7.8 (m, 1H), 7.6 (m,1H), 7.3 (m,10H), 6.7 (m, 1H), 5.2 (m, 3H), 4.0 (m, 2H), 3.3 (s, 3H),3.1 (m, 2H), 1.1 (m, 3H) TLC (7/3 hexanes/ethyl acetate) Rf=0.6.

Step 5:

To a cooled (5° C.) solution of 15.7 g (0.031 mol) of(3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-(toluene-4-sulfonyl)-aceticacid ethyl ester dissolved in 160 mL of THF is added, dropwise, 31 mL ofa 1N solution of potassium-t-butoxide dissolved in THF. The reactionmixture is warmed to room temperature and stirred for 2 hours. Thereaction is quenched with 5 mL of water and evaporated. The residue isdissolved in 200 mL of ethyl acetate and 200 mL of water. The ethylacetate layers are dried (Na₂SO₄) and evaporated. The residue ischromatographed on 375 grams of silica gel using 7/3 hexanes/ethylacetate as the eluant. Appropriate fractions are combined and evaporatedto yield 5.57 grams of3-[3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl]-acrylic acid ethylester. ¹H NMR (CDCl₃) δ7.8 (m, 2H), 7.4 (m, 2H), 7.0 (m, 1H), 6.8 (m,1H), 6.7 (m, 1H), 5.2 (s, 2H), 4.2 (q, 2H) 3.9 (s, 3H), 1.3 (t, 3H).Mass spectrum: m/e=357 (p+1).

Step 6:

A solution of 3.96 g (0.02 mol) of tosylmethyl isocyamide in 50 mL ofTHF is cooled to −70° C. To this solution is added, dropwise 40.6 mL ofpotassium bis (trimethylsilyl)-amide (0.5M solution in toluene). Afterthe addition is complete the mixture is stirred for 45 minutes at −70°C. To this mixture is added, dropwise, a solution of 5.5 g (0.015 mol)of 3-(3-benzyloxycarbonylamino-6-methoxy pyridin-2-yl)-acetic acid ethylester dissolved in 50 mL of THF. The reaction mixture is warmed to roomtemperature and stirred for 20 hours. The reaction mixture is quenchedwith water and extracted with ethyl acetate. The organic extracts aredried (Na₂SO₄) and evaporated. The residue is chromatographed on 150 gof silica gel using 50/50 ethyl acetate/hexanes as the eluant.Appropriate fractions are combined and evaporated to yield 3.2 g of4-(benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-1H-pyrrole-3-carboxylicacid ethyl ester. ¹H NMR (CDCl₃) δ9.20 (m, 1H), 8.10 (m, 1H), 7.60 (m,1H), 7.30 (m, 5H), 6.90 (m, 1H), 6.70 (m, 1H), 5.10 (s, 2H), 4.10 (q,2H), 3.90 (s, 3H), 1.90 (s, 1H), 1.10 (t, 3H). TLC (ethyl acetate)Rf=0.9.

Step 7:

A 10 mL aliquot DMF is cooled to 5° C. To this is added 2.26 mL (0.024mol) of phosphorous oxychloride. The mixture is warmed to roomtemperature, stirred for 15 minutes and cooked to 5° C. To this solutionis added dropwise a solution 3.2 g (0.08 mol) of4-(benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-1H-pyrrole-3-carboxylicacid ethyl ester dissolved in 15 mL of DMF. The reaction mixture iswarmed to room temperature and stirred for 3 hours. The reaction mixtureis carefully poured into 100 mL of saturated sodium bicarbonate. The pHis adjusted to 8 with solid K₂CO₃ and the mixture extracted with ethylacetate. The organic extracts are dried (Na₂SO₄) and evaporated. Theresidue is chromatographed on 150 g of silica gel using ethyl acetatefollowed by 10/1 chloroform/methanol as the eluant. Appropriatefractions are combined to yield 1.46 grams of 8-methoxy-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester. ¹H NMR (CDCl₃) δ9.10 (s,1H), 8.35 (d, 1H), 8.10 (s, 1H, 7.2 (s, 1H), 7.05 (d, 1H), 4.4 (q, 2H),4.10 (s, 3H), 1.40 (t, 3H). Mass spectrum: m/e=260 (p+1). TLC (ethylacetate) Rf=0.3.

Step 8:

A solution of 0.56 grams (6.0 mmol) of 2-amino pyridine in 5 mL ofmethylene chloride is cooled to 5° C. To this is added 2.25 mL (4.5mmol) of trimethyl aluminum (2M solution in toluene). This mixture isthen stirred for 45 minutes at room temperature. This solution is thenadded dropwise to a solution of 0.4 g (1.5 mmol) of8-methoxy-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl esterdissolved in 15 mL of methylene chloride. This mixture is heated to 35°C. for 18 hours. The reaction mixture is cooled to 5° C. and quenchedwith 20 mL of saturated sodium chloride. After 30 minutes the reactionmixture is filtered. The collected solids are stirred in water and thepH is adjusted to 1.8 with 1N HCl. The mixture is filtered. The filtrateis then adjusted to pH=9.0 with 1N NaOH. A tan solid precipitate iscollected, washed with acetone and dried. This solid is triturated with50 mL of 1/1 methanol/chloroform and filtered to afforded 300 mg of2-methoxy-7H-pyrrolo [2,3-c]-[1,5]napthyridine-9-carboxylicacid-pyridin-2-yl amide. ¹H NMR (CDCIl₃) δ12.3 (s, 1H), 9.1 (s, 1H), 8.5(m, 2H), 8.4 (s, 1H), 8.3 (m, 1H), 7.85 (m, 1H), 7.2 (m, 2H), 7.1 (m,1H), 4.2 (s, 3H). Mass spectrum: m/e=320 (p+1).

Example 21c

Using the method shown in Scheme 10 and further illustrated in Example21b the compounds shown in Table 7 were prepared.

TABLE 7

Cpd# Name R3a R3 R4 Ar Spectral Data 1 2-Methoxy-7H- pyrrolo[2,3-c][1,5]naphthyridine- 9-carboxylic acid (2,4-dichloro- phenyl)-amideCH₃O H H

m/e = 308, 310 2 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid pyridin-2-ylamide CH₃O H H

m/e = 320.1 (P + 1) 3 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (3-fluoro-phenyl)- amide CH₃O H H

m/e = 337 (P + 1) 4 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (1-ethyl-1H-pyrazol- 3-yl)-amide CH₃O H H

m/e = 337 (p + 1) 5 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (4-chloro-phenyl)- amide CH₃O H H

m/e = 352, 354 6 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (4-ethoxy-phenyl)- amide CH₃O H H

m/e = 363 (p + 1) 7 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid o-tolylamide CH₃O H H

m/e = 333 (p + 1) 8 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid pyrazin-2-ylamide CH₃O H H

m/e = 435 (p + 1) 9 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (3-fluoro-4-methoxy- phenyl)-amide CH₃O H H

m/e = 367 (p + 1) 10 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (6-methoxy-2-methyl- pyridin-3-yl)-amide CH₃O H H

Mm/e = 364 (p + 1) 11 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (3-methoxy-phenyl) amide CH₃O H H

m/e = 349 (p + 1) 12 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (5-methyl-pyridin-2- yl)-amide CH₃O H H

m/e = 448 (p + 1) 13 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (2,4-difluoro- phenyl)-amide CH₃O H H

m/e = 355 (p + 1) 14 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (4-fluoro-phenyl)- amide CH₃O H H

m/e = 337 (p + 1) 15 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid p-tolylamide CH₃O H H

m/e = 333 (p + 1) 16 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (6-methoxy-pyridin- 3-yl)-amide CH₃O H H

m/e = 350 (p + 1) 17 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid (1H-pyrazol-3-yl)- amide CH₃O H H

m/e = 309 (P + 1) 18 2-Methoxy-7H- pyrrolo[2,3- c][1,5]naphthyridine-9-carboxylic acid isoxazol-3-ylamide CH₃O H H

m/e = 310 (p + 1)

Example 21d Preparation of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid(3-fluro-phenyl)-amide

Step 1:

A solution of 13.55 g (0.069 mol) of tosylmethyl isocyamide dissolved in200 mL of dry THF is cooled to −70° C. under an atmosphere of nitrogen.To this solution is added dropwise 138 mL (0.069 mol) of potassiumbis(trimethylsilyl) amide (0.5M solution in toluene) maintaining thetemperature<−65° C. After the addition is complete the mixture isstirred 1 hour at −70° C. To this solution 8.68 g (0.048 mol) of3-(3-cyano-pyridyl-2-yl) acrylic acid methyl ester (A. N. Kost, L. N.Zhukauskaite, Chem. Heterocycic Compds. English Trans., 1971, 7,469-473) dissolved in 150 mL of dry THF is added dropwise maintainingthe temperature at −65° C. The reaction mixture is stirred at −65° C.for 45 minutes and then warmed to −10° C. and stirred an additional 2hours. The reaction is quenched with 75 mL of water and extracted withethyl acetate. The organic extracts are dried (Na₂SO₄) and evaporated.The residue is chromatographed on 400 g of silica gel using ethylacetate as the eluant. Appropriate fractions are combined and evaporatedto yield 5.4 grams of 4-cyano-pyindin-2-yl-1H-pyrrole-3-carboxylic acidmethyl ester. ¹H NMR (CDCl₃) δ9.5 (s, 1H), 8.8 (m, 1H), 8.0 (m, 1H),7.45 (m, 1H), 7.35 (m, 1H), 7.05 (m, 1H), 3.7 (s, 3H). Mass spectrum:m/e=228 (p+1). TLC (ethyl acetate) Rf=0.5.

Step 2:

A solution of 30 mL (360 mmol) of DMF in 200 mL of methylene chloride iscooled to 5° C. under a nitrogen atmosphere. To this is added 16 mL (180mmol) of phosphorus oxychloride, maintaining the temperature<10° C.After addition is complete the reaction is stirred for a ½ hour. To thisis added dropwise a solution of 4.0 g (18 mmol) of4-cyano-pyridin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester dissolvedin 100 mL of methylene chloride. The reaction mixture is then heated to40° C. for 48 hours. The reaction mixture is cooled to room temperatureand slowly poured in 300 mL of saturated sodium bicarbonate. The organiclayer is then extracted from the aqueous layer, dried (Na₂SO₄) andevaporated. The residue is chromatographed on 150 grams of silica gelusing 1/1 ethyl acetate/hexanes as the eluant. Appropriate fractions arecombined to yield 0.75 g of4-(3-cyano-pyridin-2-yl)-5-formyl-1H-pyrrole-3-carboxylic acid methylester. ¹H NMR (CDCl₃) δ10.1 (s, 1H), 9.4 (s, 1H), 8.8 (m, 1H), 8.1 (m,1H), 7.75 (m, 1H), 7.5 (m, 1H), 3.75 (s, 3H) Mass spectrum: m/e=256.2(p+1). TLC (10/1 ethyl acetate/chloroform) Rf=0.7. Continued elution ofthe column afforded 2.5 grams of the starting pyrrole methyl ester.

Step 3:

A mixture of 0.75 g (2.9 mmol) of4-(3cyano-pyridin-2-yl-5-formyl-1H-pyrrole-3-carboxylic acid methylester dissolved in 40 mL of methanol containing 2 mL of concentrated HCland 500 mg of 10% Pd/C catalyst is hydrogenated at 50 PSI for 24 hours.The reaction mixture is filtered and evaporated. The residue isdissolved in a mixture of 50 mL water and ethyl acetate. The ethylacetate extracts are dried (Na₂SO₄) and evaporated to yield 0.35 gramsof recovered starting material. The pH of the water layer is adjusted to9.0 with 1N NaOH and evaporated. The residue is triturated withchloroform. The chloroform extracts are combined, dried (Na₂SO₄) andevaporated. The residue is chromatographed on 9 grams of silica gelusing 5/1 chloroform/methanol as the eluant. Appropriate fractions arecombined and evaporated to yield 180 mg of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acidmethyl ester. ¹H NMR (CDCl₃) δ10.1 (s, 1H), 8.50 (m, 1H), 7.50 (m, 1H),7.20 (s, 1H), 7.05 (m, 1H), 3.90 (s, 2H), 3.75 (s, 2H), 3.80 (s, 3H).Mass spectrum: m/e=244.3 (p+1). TLC (5/1/0.1chloroform/methanol/ammonium hydroxide) Rf=0.2.

Step 4:

To a solution of 0.38 mL (4 mmol) of 3-fluoroaniline in 2 mL ofmethylene chloride under a nitrogen atmosphere is added dropwise 1.5 mL(3 mmol) of trimethyl aluminum (2M solution of toluene). This mixture isstirred at room temperature for 30 minutes. To this mixture is added asolution of 0.12 g (0.5 mmol) of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acidmethyl ester dissolved in 8 mL of methylene chloride. The reactionmixture is heated to 40° C. for 24 hours; cooled to room temperature andquenched with 0.5 mL of saturated NaCl. After stirring for 30 minutes anadditional 5 mL of methylene chloride and 2 grams of anhydrous sodiumsulfate is added. The reaction mixture is filtered. The filtrate isevaporated and chromatographed on 10 grams of silica gel using 10/1/0.5chloroform/methanol/ammonium hydroxide as the eluant. Appropriatefractions are combined and evaporated to 23 mg of3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid(3-fluoro-phenyl)-amide. ¹H NMR (CD₃OD) δ8.70 (m, 1H), 7.90 (m, 1H),7.80 (m, 1H), 7.60 (s, 1H), 7.30 (m, 3H), 6.90 (m, 1H), 3.87 (s, 2H),3.70 (s, 2H). Mass spectrum: m/e=323.2 (p+1). TLC (10/1/0.1chloroform/methanol/ammonium hydroxide) Rf=0.3.

Example 21e Preparation of5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-2-ylamide

Step 1 (Step 4′ Scheme 11):

A mixture of 130 mg (0.53 mmol) of3,4,5,6-Tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acidmethyl ester and 0.6 mL (0.6 mmol of benzaldehyde is dissolved in 10 mLof dichloroethane. To this solution is added 270 mg (1.3 mmol) of sodiumtriacetoxyborohydride and the resulting mixture is stirred for 18 hoursat room temperature. A 10 mL solution of saturated Na₂HCO₃ is added, andthe reaction stirred for 60 minutes. The organic layer is separated fromthe aqueous layer, dried (Na₂SO₄) and evaporated. The residue ischromatographed on 10 grams of silica gel using 50/1 chloroform/methanolas the eluant. Appropriate fractions are combined to yield 118 mg of5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid methyl ester. ¹H NMR (CDCl₃) δ10.1 (s, 1H), 8.6 (d, 1H), 7.55 (d,1H), 7.3 (m, 6H), 7.1 (m, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 3.55 (s, 2H),3.35 (s, 2H). Mass spectrum: m/e 334.3 (p +1). TLC (10/1chloroform/methanol) Rf=0.15.

Step 2 (Step 5′ in Scheme 11):

To a solution of 110 mg (1.2 mmol) of 2-aminopyridine in 2 mL ofmethylene chloride is added dropwise 0.5 mL (1.0 mmol) of trimethylaluminum (2M solution in toluene). This mixture is stirred at roomtemperature for ½ hour. The resulting solution is then added dropwise toa 68 mg (0.2 mmol) solution of5-Benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid methyl ester dissolved in 8 mL of methylene chloride and themixture heated to 40° C. for 4 hours. The reaction mixture is quenchedwith the dropwise addition of 0.75 mL of 1N NaOH and then dried withanhydrous Na₂SO₄ The reaction mixture is filtered, and the filtrateevaporated. The residue is chromatographed on 9 grams of silica gelusing 50/1 chloroform/methanol as the eluant. Appropriate fractions arecombined and evaporated to yield 65 mg of5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-2-ylamide. ¹H NMR (CDCl₃) δ14.1 (s, 1H), 11.0 (s, 1H), 8.8(m, 1H), 8.4 (m, 2H), 7.7 (s, 1H), 7.6 (m, 2H), 7.4 (m, 6H), 6.95 (m,1H), 3.7 (s, 2H), 3.55 (s, 2H), 3.50 (s, 2H). Mass spectrum: m/e=396.3(p+1). TLC (10/1 chloroform/methanol) Rf=0.6

Example 21f Preparation of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylicacid pyridin-2-yl-amide.

Step 1:

A mixture of 11.3 g (0.069 mol) of 2-methyl-nicotinic acid ethyl esterand 8.4 g (0.076 mol) of selenium dioxide in 150 mL of dioxane isrefluxed under nitrogen for 4 hours. The reaction mixture is cooled toroom temperature and filtered. The filtrate is evaporated and theresidue is chromatographed on 400 grams of silica gel using 50/50 ethylacetate/hexanes as the eluant. Appropriate fractions are combined toyield 5 g of 2-formyl-nicotinic acid ethyl ester. ¹H NMR (CDCl₃) δ10.3(s, 1H), 8.8 (m, 1H), 8.0 (m, 1H), 7.5 (m, 1H), 4.30 (q, 2H), 1.4 (t,3H). TLC (7/3 hexanes/ethyl acetate) Rf=0.2.

Step 2:

A mixture of 15.4 g (0.086 mol) of 2-formyl-nicotinic acid ethyl esterand 17.9 g (0.094 mol) of p-toluene-sulfonic-acid-monohydrate dissolvedin 150 mL of methanol is refluxed for 8 hours. The reaction mixture iscooled to room temperature and the solvent evaporated. The residue isadded to water and the pH adjusted to 9.0 with 1N NaOH. The water isextracted with ethyl acetate. The ethyl acetate extracts are dried(Na₂SO₄) and evaporated. The residue is chromatographed on 400 g ofsilica gel using 1/1 ethyl acetate/hexanes as the eluant. Appropriatefractions are combine and evaporated to yield 11.25 grams of2-dimethoxymethyl-nicotinic acid ethyl ester. ¹H NMR (CDCl₃) δ8.70 (d,1H), 8.0 (d, 1H), 7.2 (m, 1H), 6.0 (s, 1H), 4.3 (q, 2H), 3.4 (s, 6H),1.3 (t, 3H).

Step 3:

A mixture of 11.3 g (0.05 mol) of 2-dimethoxymethyl-nicotinic acid ethylester dissolved in 150 mL of ether and 2.09 g (0.055 mol) of lithiumaluminum hydride is stirred at room temperature for 18 hours. Anadditional 530 mg of lithium aluminum hydride is added and the reactionmixture stirred for another 3 hours. The reaction mixture is cooledusing an ice bath and quenched with 6 mL of 1N NaOH and 8 g of sodiumsulfate decahydrate. After a ½ hour the reaction mixture is filtered andthe filtrate evaporated. The residue is chromatographed on 180 g ofsilica gel using ethyl acetate as the eluant. Appropriate fractions arecombined and evaporated to yield 4.45 g of(2-dimethoxymethyl-pyridin-3-yl) methanol. ¹H NMR (CDCl₃) δ8.40 (d, 1H),7.70 (d, 1H), 7.20 (m, 1H), 5.35 (s, 1H), 4.75 (s, 2H), 3.40 (s, 3H).

Step 4:

A mixture of 321 mg (1.75 mmol) of(2-dimethoxymethyl-pyridin-3-yl)-methanol and 763 mg (8.77 mmol) of MnO₂in 10 mL of toluene is refluxed for 1.5 hours. The reaction mixture iscooled to room temperature and filtered. The filtrate is evaporated toyield 271 mg of 2-dimethoxymethyl-pyridine-3-carbaldehyde. ¹H NMR(CDCl₃) δ10.30 (s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.30 (m, 1H), 5.40(s, 2H), 4.40 (s, 6H).

Step 5:

To a mixture of 2.0 g (11 mmol) of2-dimethoxymethyl-pyridin-3-carbaldehyde and 1.6 mL (12 mmol) ofN-benzyl methyl amine in 30 mL of dichloroethane is added 4.7 g (22mmol) of sodium triacetoxyborohydride. The reaction is stirred for 18hours at room temperature. To this mixture is added 20 mL of water.After 1 hour of stirring the pH of the reaction mixture is adjusted to8.0 with 1N NaOH. The organic layer is separated from the water layer,dried and evaporated to yield 1.9 grams ofbenzyl-(2-dimethoxymethyl-pyridin-3-ylmethyl)-methyl-amine. ¹H NMR(CDCl₃) δ8.5 (d, 1H), 7.9 (d, 1H), 7.3 (m, 6H), 5.6 (s, 1H), 3.7 (s,2H), 3.5 (s, 2H), 3.3 (s, 6H) 2.1 (s, 3H). Mass spectrum: m/e=287.8(p+1). TLC (1/1 ethyl acetate/hexanes) Rf=0.2.

Step 6:

A mixture of 1.9 g (6.6 mmol) ofbenzyl-(2-dimethoxymethyl-pyridin-3-yl-methyl)-methyl-amine dissolved in20 mL of acetone and 20 mL of 1N HCl is heated to 65° C. for 6 hours.The reaction mixture is cooled to room temperature and evaporated toremove the acetone. To the resulting residue is added 40 mL of ethylacetate and the pH of the mixture adjusted to 9.0 with 5N NaOH. Theorganic layer is separated from the water layer, dried (Na₂SO₄) andevaporated to afford 1.5 grams of3-(benzyl-methyl-amino)-methyl-pyridine-2-carbaldehyde. ¹H NMR (CDCl₃)δ10.1 (s, 1H), 8.7 (m, 1H), 8.15 (m, 1H), 7.45 (m, 1H), 7.25 (m, 5H),4.0 (s, 2H), 3.6 (s, 3H) 2.1 (S, 3H). TLC (1/1 ethyl acetate/hexanes)Rf=0.4.

Step 7:

A solution of 1.9 mL (9.4 mmol) of triethylphosphoro-acetate in 25 mL ofanhydrous THF is cooled to −50° C. under a nitrogen atmosphere. To thisis added dropwise 19 mL (9.5 mmol) of potassium bis(trimethylsilyl)amide (0.5M in toluene). After 10 minutes, a solution of 1.5 g (6.2mmol) of 3-(benzyl-methyl-amino)-methyl-pyridine-2-carbaldehydedissolved in 10 mL of anhydrous THF is added dropwise. After theaddition is complete the reaction mixture is warmed to room temperatureand stirred for 2 hours. The reaction is quenched with 20 mL of waterand extracted with ethyl acetate. The ethyl acetate extracts are dried(Na₂SO₄) and evaporated. The residue is chromatographed on 40 g ofsilica gel using 3/1 hexanes/ethyl acetate as the eluant. Appropriatefractions are combined and evaporated to yield 1.8 g of3-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-acrylic acid ethylester. ¹H NMR (CDCl₃) δ8.5 (d, 1H), 8.2 (d, 1H), 7.7 (m, 1H), 7.3 (m,5H), 7.1 (d, 1H), 4.3 (q, 2H), 3.65 (s, 2H), 3.55 (s, 2H), 2.10 (s, 3H),1.30 (t, 3H). Mass spectrum: m/e=311.3 (p+1). TLC (2/1 hexanes/ethylacetate) Rf=0.7.

Step 8:

A solution of 2.3 g (11.6 mmol) of tosylmethyl isocyamide in 25 mL ofanhydrous THF is cooled to −50° C. under a nitrogen atmosphere. To thissolution is added dropwise 23 mL (11.6 mmol) of potassiumbis(trimethylsilyl) amide (0.5M solution in toluene) keeping thetemperature<−50° C. After addition is complete this mixture is stirredfor a 0.5 hour. To this mixture a solution of 1.8 g (5.8 mmol) of3-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-acrylic acid ethylester dissolved in 10 mL of anhydrous THF is added dropwise maintaininga temperature<−50° C. After addition is complete the reaction mixture isquenched with 10 mL of water and extracted with ethyl acetate. Theorganic extracts are dried (Na₂SO₄) and evaporated. The residue isredissolved in approximately 100 mL of ethyl acetate and 100 mL ofwater. The pH of the mixture is adjusted to 2.0 with 1N HCL. The ethylacetate layer is separated from the water layer. An additional 100 mL ofethyl acetate is added to the water layer and the pH adjusted to 9.0with 1N NaOH. The ethyl acetate layer is separated from the water layer,dried (Na₂SO₄) and 2 evaporated to yield 1.9 grams of4-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid ethyl ester. ¹H NMR (CDCl₃) δ8.5 (m, 1H), 8.0 (m, 1H), 7.35 (s,6H), 7.30 (m, 5H), 7.20 (m, 1H), 6.60 (s, 1H), 4.0 (q, 2H), 3.42 (s,2H), 3.38 (s, 2H), 2.0 (s, 3H), 1.0 (t, 3H). Mass spectrum: m/e=350.3(p+1). TLC (10/1 chloroform/methanol) Rf=0.35.

Step 9:

A solution of 6 mL of DMF dissolved in 20 mL of methylene chloride iscooled to 5° C. under a nitrogen atmosphere. To this is added dropwise 2mL (22 mmol) of phosphorous oxychloride. The reaction is stirred at roomtemperature for 30 minutes and this solution is added to a cooled (5°C.) solution of 3-{[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-acrylicacid ethyl ester dissolved in 20 mL of methylene chloride. This mixtureis then stirred for 18 hours at room temperature. The reaction mixtureis quenched with 20 mL of saturated NaHCO₃ and extracted with ethylacetate. The organic extracts are dried (Na₂SO₄) and evaporated. Theresidue is chromatographed on 100 g of silica gel using 4/1 ethylacetate/chloroform as the eluant. Appropriate fractions are combined andevaporated to yield 1.5 g of4-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-5-formyl-1H-pyrrole-3-carboxylicacid ethyl ester. ¹H NMR (CDCl₃) δ11.1 (s, 1H), 9.2 (s, 1H), 8.6 (d,1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H) 7.2 (m, 5H), 4.0 (q, 2H),2.95 (s, 2H), 2.85 (s, 2H), 2.0 (s, 3H), 1.0 (t, 3H). Mass spectrum:m/e=378.3 (p+1). TLC (10/1 ethyl acetate/chloroform) Rf=0.6.

Step 10:

To a solution of 1.5 grams (4 mmol) of4-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-5-formyl-1H-pyrrole-3-carboxylicacid ethyl ester in 50 mL of ethanol containing 2 mL of concentrated HCLis added 500 mg of 10% Pd/C and this mixture is hydrogenated at 50 PSIfor 48 hours. The reaction mixture is filtered and the filtrateevaporated. The residue is chromatographed on 100 g of silica gel using10/1 chloroform/methanol as the eluant. Appropriate fractions arecombined to yield 495 mg of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benza(e)azulene-1-carboxylicacid ethyl ester. ¹H NMR (CDCl₃) δ8.65 (d, 1H), 7.65 (d, 1H), 7.35 (s,1H), 7.15 (m, 1H), 4.10 (q, 2H), 3.50 (s, 2H), 3.40 (s, 2H), 2.40 (s,2H), 1.20 (t, 3H). Mass spectrum: m/e=378.3 (p+1). TLC (10/1chloroform/methanol) Rf=0.15.

Step 11:

To a solution of 0.17 g (1.8 mmol) of 2-aminopyridine in 2 mL ofmethylene chloride is added 0.75 mL (1.5 mmol) of trimethyl aluminum (2Msolution in toluene) under a nitrogen atmosphere. This mixture isstirred for 0.5 hour at room temperature. This mixture is then addeddropwise to a solution of 84 mg (0.3 mmol) of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylicacid ethyl ester dissolved in 8 mL of methylene chloride. The reactionmixture is heated to 40° C. for 18 hours. The reaction mixture is cooledto room temperature and quenched with 0.2 mL of 1N NaOH. To this isadded anhydrous Na₂SO₄ and the reaction filtered. The filtrate isevaporated and the residue chromatographed on 20 g silica gel using 5/1chloroform/methanol as the eluant. Appropriate fractions are combinedand evaporated to yield 60 mg of5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benza(e)azulene-1-carboxylicacid pyridin-2-yl-amide. ¹H NMR (CDCl₃) δ13.9 (s, 1H), 11.1 (s, 1H), 8.8(m, 1H), 8.4 (m, 2H), 7.7 (m, 3H), 7.2 (m, 1H), 6.9 (m, 1H), 3.6 (s,2H), 3.4 (s, 2H), 2.4 (s, 3H). Mass spectrum: m/e=320.2 (p+1). TLC (5/1chloroform/methanol) Rf=0.5.

Example 21g

Using the method shown in Schemes 11 and 12 and further illustrated inExamples 21d-21f the compounds shown in Table 8 were prepared.

TABLE 8

Cpd# Name R3a R3 R4 R5 Ar Spectral Data 1 5-Methyl-3,4,5,6-tetrahydro-3,5,10- triaza- benzo[e] azulene-1- carboxylic acid(1H-pyrazol-3-yl)-amide H H H CH₃

m/e = 309(P = 1) 2 3,4,5,6-Tetrahydro- 3,5,10-triaza- benzo[e]azulene-1-carboxylic acid pyridin-2-ylamide H H H H

m/e = 306(p + 1) 3 5-Methyl-3,4,5,6- tetrahydro-3,5,10- triaza-benzo[e]azulene-1- carboxylic acid H H H CH₃

m/e = 320(p + 1) 4 5-Benzyl-3,4,5,6- tetrahydro-3,5,10- triaza-benzo[e]azulene-1- carboxylic acid pyridin-2-ylamide H H H

m/e = 396(p + 1) 5 5-Pyridin-2- ylmethyl-3,4,5,6- tetrahydro-3,5,10-triaza- benzo[e]azulene-1- carboxylic acid pyridin-2-ylamide H H H

m/e = 397(p + 1) 6 5-Methyl-3,4,5,6 tetrahydro-3,5,10- triaza-benzo[e]azulene-1- carboxylic acid pyridin-3-ylamide H H H CH₃

m/e = 320(p + 1) 7 5-Methyl-3,4,5,6- tetrahydro-3,5,10- triaza-benzo[e]azulene-1- carboxylic acid(3- fluoro-phenyl)-amide H H H CH₃

m/e = 337(p + 1) 8 3,4,5,6-Tetrahydro- 3,5,10-triaza- benzo[e]azulene-1-carboxylic acid(3- fluoro-phenyl)-amide H H H H

m/e = 323(P + 1) 9 5-Methyl-3,4,5,6- tetrahydro-3,5,10- triaza-benzo[e]azulene-1- carboxylic acid isoxazol-3-ylamide H H H CH₃

m/e = 310(p + 1)

Example 22 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SR¹International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 23 Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExample.

Example 24 Binding Assay

This assay is a standard assay for GABA_(A) binding affinity. The highaffinity and high selectivity of compounds of this invention for thebenzodiazepine site of the GABA_(A) receptor is confirmed using thebinding assay described in Thomas and Tallman (J. Bio. Chem. 1981;156:9838-9842, and J. Neurosci. 1983; 3:433-440).

Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) ofBuffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissuehomogenate is centrifuged in the cold (4° C.) at 20,000×g for 20minutes. The supernatant is decanted, the pellet rehomogenized in thesame volume of buffer, and centrifuged again at 20,000×g. Thesupernatant of this centrifugation step is decanted and the pelletstored at −20° C. overnight. The pellet is then thawed and resuspendedin 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g andthe supernatant decanted. This wash step is repeated once. The pellet isfinally resuspended in 50 volumes of Buffer A.

Incubations containing 100 μl of tissue homogenate, 100 μl ofradioligand, (0.5 nM ³H-RO15-1788 [³H-Flumazenil], specific activity 80Ci/mmol), and test compound or control (see below), are brought to atotal volume of 500 μl with Buffer A. Incubations are carried for 30 minat 4° C. and then rapidly filtered through Whatman GFB filters toseparate free and bound ligand. Filters are washed twice with freshBuffer A and counted in a liquid scintillation counter. Nonspecificbinding (control) is determined by displacement of ³H Ro15-1788 with 10μM Diazepam (Research Biochemicals International, Natick, Mass.). Datawere collected in triplicate, averaged, and percent inhibition of totalspecific binding (Total Specific Binding=Total−Nonspecific) iscalculated for each compound.

A competition binding curve is obtained with up to 11 points spanningthe compound concentration range from 10⁻¹²M to 10⁻⁵M obtained per curveby the method described above for determining percent inhibition. K_(i)values are calculated according the Cheng-Prussof equation. When testedin this assay, preferred compounds of Formulas I exhibit K_(i) values ofless than 1 uM, more preferred compounds of the invention have K_(i)values of less than 500 nM and highly preferred compounds have K_(i)values of less than 100 nM.

Example 25 Electrophysiology

The following assay is used to determine if a compound of the inventionact as an agonist, an antagonist, or an inverse agonist at thebenzodiazepine site of the GABA_(A) receptor.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications.Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.Xenopus Laevis oocytes are enzymatically isolated and injected withnon-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γsubunits, respectively. Of the nine combinations of α, β and γ subunitsdescribed in the White et al. publications, preferred combinations areα₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂. Preferably all of the subunit cRNAsin each combination are human clones or all are rat clones. The sequenceof each of these cloned subunits is available from GENBANK, e.g., humanα₁, GENBANK accession no. X14766, human α₂, GENBANK accession no.A28100; human α₃, GENBANK accession no. A28102; human α₅, GENBANKaccession no. A28104; human β₂, GENBANK accession no. M82919; human β₃,GENBANK accession no. Z20136; human β₂, GENBANK accession no. X15376;rat α₁, GENBANK accession no. L08490, rat α₂, GENBANK accession no.L08491; rat α₃, GENBANK accession no. L08492; rat α₅, GENBANK accessionno. L08494; rat β₂, GENBANK accession no. X15467; rat β₃, GENBANKaccession no. X15468; and rat γ₂, GENBANK accession no. L08497. For eachsubunit combination, sufficient message for each constituent subunit isinjected to provide current amplitudes of >10 nA when 1 μM GABA isapplied.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current (e.g. 1 μM-9 μM). Each oocyte isexposed to increasing concentrations of compound in order to evaluate aconcentration/effect relationship. Compound efficacy is calculated as apercent-change in current amplitude: 100*((Ic/I)−1), where Ic is theGABA evoked current amplitude observed in the presence of test compoundand I is the GABA evoked current amplitude observed in the absence ofthe test compound.

Specificity of a compound for the benzodiazepine site is determinedfollowing completion of a concentration/effect curve. After washing theoocyte sufficiently to remove previously applied compound, the oocyte isexposed to GABA+1 μM RO15-1788, followed by exposure to GABA+1 AMRO¹⁵-1788+ test compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of RO15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM RO15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values bystandard methods. To evaluate average efficacy and EC₅₀ values, theconcentration/effect data are averaged across cells and fit to thelogistic equation.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein: the b-ring is a 7membered ring with one nitrogen; E represents (CR¹R²)_(k), —CR¹═CR²—,—N═CR¹—, —CR¹═N—, —NR′—(CR¹R²)—, or —(CR¹R²)—NR′—, wherein R¹ and R²independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono- or di- (C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, or mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl, orphenyl, pyridyl, phenyl(C₁-C₆)alkyl, or pyridyl (C₁-C₆) alkyl, whereeach phenyl or pyridyl is optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- ordi(C₁-C₆)alkylamino; k is 2; R′ represents hydrogen, C₁-C₆ alkyl, C₁-C₆alkanoyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or aryl, heteroaryl, aryl(C₁-C₆)alkyl,or heteroaryl(C₁-C₆)alkyl, where each aryl and heteroaryl is optionallysubstituted with up to 3 groups independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- anddi(C₁-C₆)alkylamino; G is oxygen or NH; J represents (CR⁵R⁶)_(d) where dis 1 ; and R⁵ and R⁶ together form a carbonyl group; or R⁵ and R⁶ areindependently hydrogen or R¹⁰⁰, where each R¹⁰⁰ is independentlyselected from halogen, hydroxy, nitro, cyano, R₁₀, amino, —NH(R₁₀),—N(R₁₀)(R₁₀), —COOH, —O(R₁₀) , —SO₂NH₂, —SO₂NH(R₁₀) , —SO₂N(R₁₀)(R₁₀),—NHCO(R₁₀), —N(R₁₀)CO(R₁₀), —NHCO₂(R₁₀), —N(R₁₀)CO₂(R₁₀), —NNSO₂(R₁₀),—N(R₁₀)SO₂(R₁₀), —SO₂NHCO(R₁₀) , —SO₂N(R₁₀)CO(R₁₀), —CONHSO₂(R₁₀),—CON(R₁₀)SO₂(R₁₀), —CONH₂, —CONH(R₁₀), —CON(R₁₀)(R₁₀), —CO₂(R₁₀),—CO(R₁₀), —SR₁₀, SO(R¹⁰), —SO₂(R₁₀), aryl having from 1 to 3 rings, andheteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ringmembers in each ring, and in at least one of said rings from 1 to about3 heteroatoms selected from nitrogen, oxygen and sulfur, and where eacharyl and heteroaryl is optionally substituted with 1, 2, or 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- or di(C₁-C₆)alkylamino; each R₁₀ isindependently a straight, branched, or cyclic alkyl group having up to 8carbon atoms, contains zero or one or more double or triple bonds, andis optionally substituted with one or more substituents independentlyselected from hydroxy, oxo, halogen, amino, mono- ordi-(C₂-C₆)alkylamino, cyano, nitro, C₁-C₆alkoxy, —COOH, —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)(C₁-C₆alkyl), —NHCO(C₁-C₆alkyl),—N(C₁-C₆alkyl)CO(C₁-C₆alkyl), NHCO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)CO₂(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)SO₂(C₁-C₆alkyl), —SO₂N(C₁-C₆alkyl)CO(C₁-C₆alkyl),—SO₂NHCO(C₁-C₆alkyl), —CON(C₁-C₆alkyl)SO₂(C₁∝C₆alkyl),—CONHSO₂(C₁-C₆alkyl), —CONH₂, —CONH(alkyl), —CON(alkyl)(alkyl),—CO₂(alkyl), —CO(alkyl), —SO₀₋₂(C₁-C₆alkyl), and C₃-C₇cycloalkyl; thegroup

 is the A ring and represents an optionally substituted saturated,partially unsaturated, or aromatic heterocyclic ring containing at leastone nitrogen, oxygen, or sulfur atom, where the A ring is optionallysubstituted with up to three groups independently selected from R¹⁰⁰; Vis nitrogen, carbon, or CH; Y is carbon or CH; X is hydrogen, hydroxy,amino, mono- or di(C₁-C₆) alkylamino, C₁-C₆alkyl, or C₁-C₆ alkoxy; T ishydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆) alkylamino, C₁-C₆alkyl, or C₁-C₆ alkoxy; Q is a saturated carbocyclic or heterocyclicgroup, partially unsaturated carbocyclic or heterocyclic group, an arylgroup, or heteroaryl group, where each group has from 1 to 3 rings whereeach ring contains from 3 to 8 ring members, and where each heterocyclicand heteroaryl group contains at least one ring having from 1 to 3heteroatoms selected from nitrogen, oxygen and sulfur; and where eachcarbocyclic, heterocyclic, aryl, or heteroaryl group is optionallysubstituted with 1, 2, or 3 groups independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, hydroxy, oxo, cyano, nitro, amino, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, and mono- or di(C₁-C₆) alkylamino; W is abond, oxygen, NH, sulfur, —CH═CH—, —C≡C—, or CR⁷R⁸ where R⁷ and R⁸ arethe same or different and represent hydrogen, C₁-C₆ alkyl,halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or C₁-C₆alkoxy(C₁-C₆)alkyl, or CR⁷R⁸ represents C₃-C₇ cycloalkyl; Z is hydrogen,hydroxy, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkoxy, —CO(C₁-C₆)alkyl, C₃-C₇cycloalkyl, C₃-C₇ cycloalkyl (C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₆)alkoxy, amino, mono- or di(C₁-C₆) alkylamino, or NR₁₁COR₁₂ where R₁₁ and R₁₂ are the same or different and represent hydrogenor C₁-C₆ alkyl, or NCOR₁₁R₁₂ represents a heterocycloalkanone ring, or Zis a saturated carbocyclic or heterocyclic group, a partiallyunsaturated carbocyclic or heterocyclic group, an aryl group, or aheteroaryl group, where each group has from 1 to 3 rings where eachsaturated ring contains from 3 to 8 ring members and each aromatic orpartially unsaturated ring contains from 5-8 ring members, and whereeach heterocyclic and heteroaryl group contains at least one ring havingfrom 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; andwhere each carbocyclic, heterocyclic, aryl, and heteroaryl group isoptionally substituted with 1, 2, or 3 groups independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and mono- or di(C₁-C₆)alkylamino;

 independently represent saturated carbon chains optionally substitutedwith one or more substituents independently selected from halogen,cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkyl,and C₃-C₇ cycloalkyl; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3;provided that when V is nitrogen, E does not contain nitrogen.
 2. Acompound or salt according to claim 1, wherein G is NH; E represents(CR¹R²)_(k); the A ring represents a group of the formula:

 which represents a saturated, partially unsaturated, or aromaticheterocyclic ring selected from thienyl, thiazolyl, pyridyl, pyridonyl,pyrimidinyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl,piperidinyl, oxazolyl, isoxazolyl, triazolyl, pyrrolyl, furanyl,diazenyl, triazenyl, 1,2,4-triazolone, 4,5-dihydroimidazolyl, and1,4,5,6-tetrahydropyrimidinyl, where any amino-hydrogen is optionallyreplaced by R^(A) where: U is nitrogen, NR^(A), S, or O; V is nitrogen,carbon or CH; Y is carbon, or CH; R^(A) is selected from (C₁-C₆)alkyl,C₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, where each aryl and heteroaryl is optionallysubstituted with up to 3 groups independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino; R³ and R⁴ are substituents on carbon atoms andindependently carry the same definitions as R⁵ and R⁶; and q is 1 or 2;R⁵ and R⁶ are independently hydrogen or R₁₀₀ where each R₂₀₀ isindependently selected from the group consisting of halogen, hydroxy,nitro, cyano, (C₁-C₆)alkyl, amino, C₁-C₆ haloalkyl, —COOH, —SO₂NH₂,—NH((C₁-C₆)alkyl₁), —N((C₁-C₆)alkyl₁)((C₁-C₆)alkyl₁), —O((C₁-C₆)alkyl₁),—SO₂N((C₁-C₆)alkyl₁)((C₁-C₆)alkyl₁), —SO₂NH((C₁-C₆)alkyl₁),—NHCO((C₁-C₆)alkyl₁), —N((C₁-C₆)alkyl₁)CO((C₁-C₆)alkyl₁),—NHCO₂((C₁-C₆)alkyl₁), —N((C₁-C₆)alkyl₁)CO₂((C₁-C₆)alkyl₁),—NHSO₂((C₁-C₆)alkyl₁), —N((C₁-C₆)alkyl₁) SO₂((C₁-C₆)alkyl₁),—SO₂NHCO((C₁-C₆)alkyl₁), —CONH₂, —SO₂N((C₁-C₆)alkyl₁)CO((C₁-C₆)alkyl₁),—CO₂((C₁-C₆)alkyl₁), —CONHSO₂((C₁-C₆)alkyl₁),—CON((C₁-C₆)alkyl₁)SO₂((C₁-C₆)alkyl₁), —CONH((C₁-C₆)alkyl₁),—CON((C₁-C₆)alkyl₁)((C₁-C₆)alkyl₁), —CO((C₁-C₆)alkyl₁), and—SO₀₋₂((C₁-C₆)alkyl₁); wherein each alkyl₁ group is C₁-C₆ alkyloptionally substituted with up to three substituents independentlyselected from hydroxy, oxo, halogen, amino, mono- ordi-(C₁-C₆)alkylamino, cyano, nitro, C₁-C₆alkoxy, —SO₂NH((C₁-C₄)alkyl),—NHCO((C₁-C₄)alkyl), —COOH, —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂NH₂,—CONH₂, —N((C₁-C₄)alkyl)CO(C₁-C₄)alkyl), —NHSO₂((C₁-C₄)alkyl),—N((C₁-C₄)alkyl)CO₂((C₁-C₄)alkyl), —CONH((C₁-C₄)alkyl),—NHCO₂((C₁-C₄)alkyl), —CONHSO₂((C₁-C₄)alkyl), —CO((C₁-C₄)alkyl),—N((C₁-C₄)alkyl)SO₂((C₁-C₄)alkyl), —SO₂NHCO((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)CO((C₁-C₄)alkyl),—CON((C₁-C₄)alkyl)SO₂((C₁-C₄)alkyl), —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl),—CO₂((C₁-C₄)alkyl), —SO₀₋₂((C₁-C₄)alkyl), and (C₃-C₇) cycloalkyl; Q isphenyl, naphthyl, quinolinyl, thienyl, pyridyl, pyridonyl, pyrimidinyl,pyrimdinonyl, piperazinyl, pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyrazolyl, furanyl, diazenyl, triazenyl, ortriazolopyrazinyl group, each of which is unsubstituted or substitutedwith up to three substituents independently selected from R₁ and R₁₁wherein R₁ represents hydroxy, cyano, halogen, nitro, amino, mono- ordi(C₁-C₆)alkylamino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy; and R₁₁ represents (C₁-C₆)alkylwhich optionally contains 1-2 heteroatoms selected from nitrogen, sulfurand oxygen and is optionally substituted with one or more carbocyclic orheterocyclic groups; Z is hydrogen, hydroxy, straight or branched chain(C₁-C₆)alkoxy, (C₃-C₇) cycloalkyl, (C₃-C₇) cycloalkyl(C₁-C₃)alkoxy,amino, mono or di(C₁-C₆)alkylamino, or NR₁₁COR₁₂ where R₁₁ and R₁₂ arethe same or different and represent hydrogen or straight or branchedchain (C₁-C₆)alkyl, or NR₁₁COR₁₂ represents a C₃-C₇ heterocycloalkanonering, or Z is phenyl, napthyl, quinolinyl, thienyl, thiazolyl, pyridyl,piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, pyrimidinyl,imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl, piperidinyl, oxazolyl,isoxazolyl, thiadiazolyl, triazolyl, oxadiazolyl, pyrrolyl, furanyl,pyrimidinyl, diazenyl, triazenyl, 1,2,4-triazolone,4,5-dihydroimidazolyl, or 1,4,5,6-tetrahydropyrimidinyl, each of whichis optionally substituted with one, two or three groups independentlyselected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro,amino, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and mono- ordi(C₁-C₆)alkylamino;

 independently represent saturated carbon chains optionally substitutedwith one, two or three substituents.
 3. A compound or salt according toclaim 2, wherein U is nitrogen, NR^(A), S, or O; V is nitrogen, carbonor CH; and Y is carbon, or CH.
 4. A compound according to claim 1, whichhas the formula:

wherein M is NR′; D is nitrogen or CR³ where R^(3a) and, each R³independently represents hydrogen, halogen, hydroxy, cyano, nitro,amino, mono- or di(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxy,amino(C₁-C₆) alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl, aryl,heteroaryl, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, or C₁-C₆ alkyl substituted with aryl or heteroaryl;and R^(5a) and R^(5b) are independently hydrogen, hydroxy, halogen,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, or mono- ordi(C₁-C₆)alkylamino, or phenyl, pyridyl, phenyl(C₁-C₆)alkyl, orpyridyl(C₁-C₆)alkyl where each phenyl and pyridyl is optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano,nitro, amino, and mono- or di(C₁-C₆)alkylamino; R′ is hydrogen, C₁-C₆alkyl, , C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or aryl, heteroaryl, aryl(C₁-C₆) alkyl,or heteroaryl(C₁-C₆)alkyl, where each aryl and heteroaryl is optionallysubstituted with up to 3 groups independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- anddi(C₁-C₆)alkylamino.
 5. A compound according to claim 4, wherein D isCR³.
 6. A compound according to claim 4, wherein D is nitrogen.
 7. Acompound according to claim 5 or 6, where R⁵ and R⁶ are independentlyhydrogen or C₁-C₆ alkyl; M is NR′ where R′ is hydrogen, C₁-C₆ alkyl, ,C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,amino(C₁-C₆)alkyl, or mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl, or aryl,heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, where each aryland heteroaryl is optionally substituted with up to 3 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, and mono- and di(C₁-C₆)alkylamino; R^(5a) andR^(5b) are hydrogen.
 8. A compound according to claim 7, wherein X and Tare hydrogen; and R^(3a) and each R³ independently represent hydrogen,halogen, hydroxy, cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, or phenyl, pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆alkyl substituted with phenyl, pyridyl, or pyrimidinyl, or imidazolyl,where each phenyl, pyridyl, pyrimidinyl, and imidazolyl is optionallysubstituted with one or two groups independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, hydroxy, and amino.
 9. A compoundaccording to claim 8, wherein each each R³ is hydrogen and R^(3a) ishydrogen, C₁-C₆ alkyl, halogen, hydroxy, C₁-C₆ alkoxy, amino or mono- ordi(C₁-C₆)alkylamino.
 10. A compound according to claim 9, where R^(3a)is hydrogen, C₁-C₆ alkyl, hydroxy, or C₁-C₆ alkoxy.
 11. A compoundaccording to claim 10, where R′ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkylsubstituted with phenyl or pyridyl, where each phenyl or pyridyl isoptionally substituted with halogen, hydroxy, amino, C₁-C₆ alkyl orC₁-C₆ alkoxy.
 12. A compound according to claim 5 or 6, wherein X and Tare hydrogen; and R^(3a) and each R³ independently represent hydrogen,halogen, hydroxy, cyano, nitro, amino, mono- or di(C₁-C₆)alkylamino,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, or nitro(C₁-C₆)alkyl, or phenyl,pyridyl, pyrimidinyl, imidazolyl, or C₁-C₆ alkyl substituted withphenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl,pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with oneor two groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, and amino.
 13. A compound according to claim 12,wherein each each R³ is hydrogen and R^(3a) is hydrogen, C₁-C₆ alkyl,halogen, hydroxy, C₁-C₆ alkoxy, amino or mono- or di(C₁-C₆)alkylamino.14. A compound according to claim 13, where R^(3a) is hydrogen, C₁-C₆alkoxy, hydroxy, or C₁-C₆ alkoxy.
 15. A compound according to any one ofclaim 2, wherein the b ring has the formula:

wherein M is NR′ or oxygen; and R^(5a) and R^(5b) are independentlyhydrogen, hydroxy, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,amino, or mono- or di(C₁-C₆)alkylamino, or phenyl, pyridyl,phenyl(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl, where each phenyl andpyridyl is optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, and mono- or di(C₁-C₆)alkylamino;and R′ is hydrogen or C₁-C₆ alkyl.
 16. A compound according to claim 15,where R⁵ and R⁶ are independently hydrogen or C₁-C₆ alkyl; M is NR′where R′ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, c₁-C₆ haloalkyl, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, or aryl, heteroaryl, aryl(C₁-C₆)alkyl,or heteroaryl (C₁-C₆)alkyl, where each aryl and heteroaryl is optionallysubstituted with up to 3 groups independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- anddi(C₁-C₆)alkylamino; and R^(5a) and R^(5b) are hydrogen.
 17. A compoundaccording to claim 16, wherein X and T are hydrogen.
 18. A compoundaccording to claim 17, where R′ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkylsubstituted with phenyl or pyridyl, where each phenyl or pyridyl isoptionally substituted with halogen, hydroxy, amino, C₁-C₆ alkyl orC₁-C₆ alkoxy.
 19. A compound according to claim 15, wherein R⁵ and R⁶are both hydrogen, X is hydrogen or methyl, R^(5a) and R^(5b) areindependently hydrogen or C₁-C₂ alkyl, M is NR′ where R′ is methyl, and

represents pyridyl or pyrazolyl, each of which is optionally substitutedwith C₁-C₃ alkyl.
 20. A compound of the formula:

wherein E represents (CR¹R²)_(k), wherein R¹ and R² are the same ordifferent and independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl; and k is 2; R³ and R⁴ independentlycarry the same definitions as R⁵ and R⁶; R⁵ and R⁶ together form acarbonyl group; or R⁵ and R⁶ are independently chosen from hydrogen,halogen, hydroxy, nitro, cyano, R₁₀, amino, C₁-C₆ haloalkyl, —NH(R₁₀),—N(R₁₀)(R₁₀), —COOH, —O(R₁₀), —SO₂NH₂, —SO₂NH(R₁₀), —SO₂N(R₁₀)(R₁₀),—NHCO(R₁₀), —N(R₁₀)CO(R₁₀), —NHCO₂(R₁₀), —N(R₁₀)CO₂(R₁₀), —NHSO₂(R₁₀),—N(R₁₀)SO₂(R₁₀), —SO₂NHCO(R₁₀), —SO₂N(R₁₀)CO(R₁₀), —CONHSO₂(R₁₀),—CON(R₁₀) SO₂(R₁₀), —CONH₂, —CONH(R₁₀), —CON(R₁₀)(R₁₀), —CO₂(R₁₀),—CO(R₁₀), —SO₀₋₂(R₁₀), carbocyclic aryl having from 1 to 3 rings, andheteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ringmembers in each ring, and in at least one of said rings from 1 to about3 heteroatoms selected from nitrogen, oxygen and sulfur, and where eachsaid carbocyclic aryl or heteroaryl is optionally substituted with 1, 2,or 3 groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, and mono- or di(C₁-C₆)alkylamino;R₁₀ is independently straight, branched, or cyclic alkyl, containingzero or 1 or more double or triple bonds, and is optionally substitutedwith one or more substituents independently chosen from hydroxy, oxo,halogen, amino, mono- or di-(C₁-C₆)alkylamino, cyano, nitro,C₁-C₆alkoxy, —COOH, —SO₂NH₂, —SO₂NH(C₁-C₆alkyl),—SO₂N(C₁-C₆alkyl)(C₁-C₆alkyl), —NHCO(C₁-C₆alkyl),—N(C₁-C₆alkyl)CO(C₁-C₆alkyl), NHCO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)CO₂(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl),—N(C₁-C₆alkyl)SO₂(C₁-C₆alkyl), —SO₂N(C₁-C₆alkyl)CO(C₁-C₆alkyl),—SO₂NHCO(C₁-C₆alkyl), —CON(C₁-C₆alkyl) SO₂(C₁-C₆alkyl),—CONHSO₂(C₁-C₆alkyl), —CONH₂, —CONH(alkyl), —CON(alkyl)(alkyl),—CO₂(alkyl), —CO(alkyl), —SO₀₋₂(C₁-C₆alkyl), and C₃-C₇cycloalkyl; T ischosen from hydrogen, halogen, hydroxy, amino, (C₁-C₆)alkyl, and(C₁-C₆)alkoxy; and R^(B) is chosen from hydrogen, methyl, ethyl andbenzyl.
 21. A compound according to claim 1, which is selected from thegroup consisting of:5-Methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid (1H-pyrazol-3-yl)-amide;3,4,5,6-Tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acidpyridin-2-ylamide;5-Methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-2-ylamide;5-Benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-2-ylamide;5-Pyridin-2-ylmethyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-2-ylamide;5-Methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid pyridin-3-ylamide;5-Methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid (3-fluoro-phenyl)-amide;3,4,5,6-Tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid(3-fluoro-phenyl)-amide;5-Methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylicacid isoxazol-3-ylamide.
 22. A compound according to claim 1 where Q isphenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, thiadiazolyl,quinolinyl, pyrazolyl, isoxazolyl, pyrazinyl, triazolyl (C₁-C₆)alkyl,pyridazinyl, 2-oxo-3-hydropyridyl, oxazole, oxadiazolyl,benzimidazol-5-yl, each of which is optionally substituted with 1, 2 or3 groups independently selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylthio, C₁-C₆alkylamino, C₃-C₇ cycloalkylamino, C₃-C₇ cycloalkyl(C₁-C₃)alkylamino,C₁-C₆ alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, furanyl, (4-benzylpiperidinyl)(C₁-C₆)alkoxy,(4-benzylpiperazinyl)(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, trifluoromethyl, C₁-C₆ haloalkoxy,1,3-dioxolanyl, ethyl-methanesulfonylamino(C₁-C₆)alkoxy, 1,4-dioxepinyl,1,4-dioxanyl, phenyoxy, pyrrolidinyl(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, C₁-C₄ alkylamino(C₁-C₄)alkyl, imidazolyl,imidazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkoxy, triazolyl(C₁-C₆)alkyl,benzyloxy(C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, azetidinyl(C₁-C₆)alkoxy,azetidinyl(C₁-C₆)alkyl, C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, C₁-C₆alkanoyl(C₁-C₆)alkoxy, C₁-C₆ alkoxyphenoxy, phenoxy substituted withhalo(C₁-C₆)alkyl, tetrahydrofuranyloxy, oxetanyl(C₁-C₆)alkoxy,oxetanyl(C₁-C₆)alkyl, and 1-benzylimidazolyl(C₁-C₆)alkoxy.
 23. Acompound according to claim 20, wherein E is —CH₂CH₂—; R³, R⁴, R⁵, andR^(6,) are independently hydrogen, halogen, amino, hydroxy, methyl,ethyl, methoxy, or ethoxy; and X and T are independently hydrogen,methyl, or ethyl.
 24. A compound according to claim 20, where Q isphenyl, pyridyl, pyrimidinyl, 2-oxo-3-hydropyridyl, each of which isoptionally substituted with 1 or 2 groups independently selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₃)alkyl, C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₃-C₇cycloalkylamino, C₃-C₇ cycloalkyl(C₁-C₃)alkylamino, C₁-C₆alkoxycarbonylamino(C₁-C₆)alkyl), C₁-C₆alkoxycarbonyl((C₁-C₆)alkyl)amino(C₁-C₆)alkyl), C₁-C₆alkylamino(C₁-C₆)alkoxy, furanyl, (4-benzylpiperidinyl)(C₁-C₆)alkoxy,(4-benzylpiperazinyl)(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkylamino,morpholinyl(C₁-C₆)alkoxy, trifluoromethyl, C₁-C₆ haloalkoxy,1,3-dioxolanyl, ethyl-methanesulfonylamino(C₁-C₆)alkoxy, 1,4-dioxepinyl,1,4-dioxanyl, phenyoxy, pyrrolidinyl(C₁-C₆)alkoxy, hydroxy(C₁-C₆alkyl,hydroxy(C₁-C₆)alkoxy, C₁-C₄ alkylamino(C₁-C₄)alkyl, imidazolyl,imidazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkoxy, triazolyl(C₁-C₆)alkyl,benzyloxy(C₁-C₆)alkoxy, piperindinyl(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl, azetidinyl(C₁-C₆)alkoxy,azetidinyl(C₁-C₆)alkyl, C₁-C₄ alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, C₁-C₆alkanoyl(C₁-C₆)alkoxy, C₁-C₆ alkoxyphenoxy, phenoxy substituted withhalo(C₁-C₆)alkyl, tetrahydrofuranyloxy, oxetanyl(C₁-C₆) alkoxy,oxetanyl(C₁-C₆)alkyl, and 1-benzylimidazolyl(C₁-C₆)alkoxy.
 25. Acompound according to claim 20, wherein R³, R⁴, R⁵, and R⁶, areindependently hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy,or ethoxy; and X and T are independently hydrogen, methyl, or ethyl. 26.A compound or salt according to claim 25, wherein R¹, R₃, R₄, R₅, and R₆are hydrogen.
 27. A compound or salt according to claim 25, wherein R¹,R², R₃, R₄, R₅, and R₆ are hydrogen.